Alexander Levitzki, Ph.D Professor Wolfson family Professor of Biochemistry

Education
1963 M.Sc. in Chemistry and Bacteriology (Biochemistry Major) Summa cum Laude, The Hebrew University of Jerusalem, Israel.
1968 Ph.D. in Chemistry (Biochemistry and Biophysics) Summa cum Laude, The Hebrew University of Jerusalem, Israel and The Weizmann Institute of Science, Rehovot, Israel.
1968-1971 Post-doctoral Fellow, Department of Biochemistry, University of California at Berkeley, Berkeley, California, with Professor D. E. Koshland, Jr.
Academic Appointments

The Weizmann Institute of Science

1970 Senior Scientist, Department of Biophysics.
1974-1976 Associate Professor (tenure).

The Hebrew University of Jerusalem

1974 Associate Professor.
1976 Professor.

Foreign Appointments

1974 Visiting Professor of Chemistry and Research Associate, Institute of Molecular Biology, The University of Oregon, Eugene, Oregon.
1974 Visiting Professor of Biochemistry, University of California at Berkeley.
1979-1980 Visiting Scientist, The National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
1984-1985 Fogarty Scholar-in-Residence, National Institutes of Health, Bethesda, MD.
1993-1994 Visiting Scholar, Stanford University, Stanford, California
2001-2003 Visiting Professor, Comprehensive Cancer Center, UCSF, San Francisco
Foreign Appointments

1974 Visiting Professor of Chemistry The University of Oregon, Eugene, Oregon.
1974 Visiting Professor of Biochemistry, University of California at Berkeley.
1979-1980 Visiting Scientist, The National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
1984-1985 Fogarty International Scholar-in- Residence, National Institutes of Health, Bethesda, MD.
1994-1995 Visiting Scholar, Stanford University, Stanford, California
2001,2002,2004 Visiting Professor, Comprehensive Cancer Center, UCSF, San Francisco
2008 Miller Professor, The University of California, Berkeley

Awards and Honors
1968-1971 Fulbright-Hayes Fellowship.
1975 Bi-Annual Shlomo Hestrin Prize of the Israel Biochemical Society.
1978 Elected as a member of EMBO (European Molecular Biology Organization).
1982 Fogarty Scholar-in-Residence Award.
1983 Bronze Medal for Biochemistry, Free University of Brussels.
1985 Chair, Wolfson Professor of Biochemistry, Hebrew University.
1985 Honorary Member of the American Society of Biological Chemists.
1990 The Israel Prize in Biochemistry.
1990 The Rothschild Prize in Biology.
1991 FEBS Lectureship Award.
1998 Schender Prize for Pharmacology and Drug Research.
1998 Lichtenstein Memorial Lecture.
1998-2001 Director, The Institute for Advanced Studies, The Hebrew University of Jerusalem.
1999 Member, Israel Academy of Sciences.
1999 Vice-President, The Federation of Israeli Societies of Experimental Biology.
2002-2005 President, The Federation of Israeli Societies of Experimental Biology.
2002 Hamilton-Fairley Award, European Society of Medical Oncology.
2003 Medal of the University, University of Helsinki.
2003 Al Wolf Lectureship (IRSC), Australia.
2004 Chairman, The Division of Natural Sciences at the Israel Academy of Sciences.
2005 The Wolf Prize for Medicine.
2005 John H Blaffer Endowed Professorship University of Texas, M.D. Anderson Cancer Center
2006 Honorary Scholar, Tel-Hai Academic College, Tel Hai, Israel.
2006

The Jacqueline Seroussi Memorial Foundation for Cancer Research Award, Tel-Aviv,Israel

2006 Prostate Cancer Foundation Research Award 2006
2006 Doctor Honoris Causa , Ben-Gurion University
2007 Member of the Board of Governors, Israel Cancer Association
2007 Prostate Cancer Foundation Research Award 2007
2008 Visiting Miller Research Professor, Miller Institute for Basic Research in Science, University of California at Berkeley.
2008 Paul Ehrlich Magic Bullet Lifetime Achievement Award in Oncology, 100th anniversary Paul Ehrlich meeting, Nuremberg, Germany ,
2010 Member, Academia Europea.
2011 Karl Friedrich Bonhoeffer Lecture, Max Plank Institute for Biophysical Chemistry, Goettingen
2012 The Nauta Award in Pharmacochemistry, The European Federation of Medicinal Chemistry (EFMC).
2013 Seventh Annual American Association for Cancer Research ,AACR, Award for Outstanding Achievement in Chemistry in Cancer Research.
2014 Ilse & Helmut Wachter-award in Medical Sciences, Innsbruck, Austria
Editorial Boards of Journals
1975-1981 European Journal of Biochemistry, Belgium.
1982-1985 Molecular Physiology, Belgium.
1982-1994 Journal of Cyclic Nucleotide Research, USA.
1987- Cellular Signalling (Associate Editor), UK.
1987-1991 Current Topics in Cellular Regulation (Editor), USA.
1991- Pharmacology (Switzerland).
1993-1996 Science, U.S.A.
1995-2002 Anti-cancer Drug Design
1998-2001 Molecular Biology Research Communications.
2000 European Journal of Chemical Biology (ChemBiochem).
2002 Oncology Research, USA.
2003

Journal of Biological Chemistry, U.S.A

2006 Current Signal Transduction Therapy, U.S.A.
Biotechnology
1982-1986 Biotechnology Research Consultants (BRC), Tel-Aviv, Senior Consultant.
1984-1988 International Diagnostic Laboratories (IDL), Jerusalem. Consultant and Member of the Board of Directors.
1987-1992 Rorer Biotechnology, King of Prussia, PA, USA, Senior Consultant.
1987-1991 Eldan-Tech, Consultant.
1993-1997 SUGEN, Inc., Redwood City, California, USA, SAB member
1993-1994 Vice President Research, SUGEN, Inc.
1995 EMBO Committee member, reviewing Biochemistry in Austria.
1997-2003

Chief scientific Advisor and member of SAB, Peptor, Ltd.

2000 Co-founder, TK Signal, Israel.
2001 Founder, Algen Biopharmaceuticals, Israel and USA.
Visit online at: http://www.algen.co.il
2001 Co-founder, UnResto (PDGFR kinase inhibitors for Restenosis).
2002-2005 ProteoLogics, Rehovot Israel, member of SAB.
2005 Founder, NovoTyr Pharmaceuticals.
2008 - 2012

Member of the Scientific Advisory Board, Teva Pharmaceutical Industries Ltd.

2015 Member SAB, Predictive Therapeutics, Inc.
2015 Member of the SAB, Protalix BioTherapeutics , Inc.
2016 Co-Founder, TargImmune Therapeutics AG, Basel, Switzerland
Others

In Israel:

  • Secretary of the Society for the Advancement of Science of Israel (1966-67)
  • Chairman, Union of the  Academic Staff of the Weizmann Institute of Science

(1972-73)

  • Chairman of the Department of Biological Chemistry (1980-84)
  • Founder and Director, Interdepartmental Equipment Facility, The Silberman Institute of Life Sciences (1980-84)
  • Chairman, University Committee for Infrastructure and Equipment(1984-88)
  • Elected (by the Senate) as member of the standing committee (1988-90)
  • Elected (by the Senate) Member of the Executive committee of the Hebrew University (1995-98)
  • Chairman, The Alexander Silberman Institute of Life Sciences (1990-93)
  • Director of The Institute of Advanced Studies, The Hebrew University of Jerusalem (1998-2001)
  • Head of the Science Section, The Israel Academy of Sciences (2005-08)
  • Member of the Board of Governors, Israel Cancer Association (2008-)

International:

  • Chairman sub-Group on non-covalent Regulation, International Union of Biochemistry (1985-89)
  • Member of the EMBO Council (1988-94)
  • Chairman, program committee, IUB International Congress of Biochemistry  (1991)
  •  Chair, Interest Group on Metabolic Regulation and Hormonal Control, IUB (1991-2000)
  • Member of International EMBO committees evaluating life sciences in Austria (1999) and Spain (2005, 2008/9)
1963-1972 : Polyamino acid as enzyme model. Levitzki started his career as a biophysicist-biochemist when he generated Cu(II) complexes of Polyhistidine as a model enzyme system to stoneudy redox enzymes.
1968- Demonstration of the validity of the “induced fit” hypothesis, using Concanavalin A: Mn2+ induces the Ca2+ site, which in turn induces the formation of the sugar binding site . These findings predicted exactly the findings by X-ray crystallography performed years later.
1968-1980s-Levitzki studied in detail the molecular basis of “negative cooperativity” and established the molecular basis this phenomenon in collaboartin with Daniel E. Koshland ,Jr. and later in his own laboratory . He was the first to demonstrate (initially with D.E.Koshland, Jr) “half-of-the-sites” reactivity in enzymes , later to be found in many oligomeric proteins, including receptors  and transcription factors. This property of many oligomeric proteins allows a symmetric oligomer to function asymmetrically, therefore being able to interface with different macromolecular entities. He also studied in detailed the molecular mechanisms of allosteric activation; these remain the only very detailed mechanistic studies on allosteric activation in enzymes thus far. The crystallographic studies on alpha-amylase and the very recent crystallographic work on CTP synthetase confirmed all the solution studies performed in the Levitzki laboratory. Levitzki developed quantitative approaches to study cooperativity by developing a rigorous mathematical methods to discriminate between molecular models of cooperativity, based on ligand competition experiments, conducted experimentally. Today it is actually well known that there are more proteins displaying negative coopertaivity than enzymes exhibiting positive cooperativity. The physiological advantages of negative cooperativity as a molecular tool for metabolic regulation, enzyme action as well the action of many receptors are well. It is interesting that negative cooperativity and half-of-the-sites reactivity have stood the test of time and today it is documented that negative coopertaivity is more frequent than the “classic” positive cooperativity. Levitzki also analyzed the phenomenon of ligand induced protein dimerization  and oligomerization, which has proved to be a general mechanism for activation of enzymes and receptors (1972). These studies constitute the theoretical basis on which many of the receptor dimerization studies were performed years later.
Levitzki published a comprehensive monograph (1978) on allosteria and cooperativity, which is widely used. It has been reproduced as an e-book (2013), by the publishers, in view of its uniqueness ,the high demand and its continued relevance.

Work on signal transduction of G protein coupled adenylyl cyclase and adrenoceptors

The Levitzki laboratory was the first to develop a radioligand binding assay on the basis of 3H-propranolol for eta-adrenoceptors, which allowed the identification of these important and ubiquitous  receptors for the first time (cited in Nature News and Views). One of the first two radioligand binding assays, using a radioactive antagonist. This work was parallel to the development of 3H-Alprenolol, 125I-pindolol and 125Icyanopindolol as radioligands for beta-adrenergic receptors in 1975. Many of the considerations to analyze binding data were developed by Levitzki . Rigorous analytical methods to examine ligand binding were formulated by Levitzki in a series of publications (1978-1980) and the book: Receptors: a Quantitative Approach ,Benjamin/Cummings(1984).
1974-1978- The first to identify the eta-adrenoceptor protein by using an effective radiolabeled  affinity label (Atlas, Steer and Levitzki 1976 PNAS 73(6) 1921-5);Atlas and Levitzki 1978 Nature 272 (5651) 370-371), which was also used effectively in the study of the mode of action of the beta adrenoceptor dependent adenylyl cyclase (see below).
1974-1990-Comprehensive analysis of the mode of adenylyl cyclase activation by G protein coupled adrenoreceptors. Levitzki discovered the “collision coupling “ mechanism (Tolkovsky and Levitzki 1978 Biochemistry 17(18) 3795-3810; Rimon, Hanski, Braun and Levitzki Nature 1978 276 (5686) 394-6;Hanski ,Rimon and Levitzki 1979 Biochemistry 18(5) 846-53; Arad, Rimon and Levitzki 1981 JBC 256(4) 1593-7), which shows that one receptor can activate dozens of Gs protein coupled cyclase molecules, constituting the first amplification step in the signaling of the beta adrenergic receptor dependent adenylyl cyclase (summarized in an invited review :Levitzki 1988 Science 241(4687) 800-8006). This was discovered in parallel to the finding (by Liebman) that one molecule of rhodopsin activates many transducin molecules. Among the issues analyzed was the molecular basis for partial agonism (Arad and Levitzki 1979 Mol Pharmacol. 16(3)749-56).The detailed mechanistic studies on the mode of coupling between beta-adrenergic  receptors with adenylyl cyclase  predicted that the Gs protein is permanently coupled to the enzyme adenylyl cyclase and that the beta/gamma subunits remain attached during the activation cycle. These kinetic/ mechanistic studies were backed up by biochemical studies (Arad, Rosenbusch and Levitzki 1984 PNAS 81 (21) 6579-83; Bar-Sinai, Marbach, Shorr and Levitzki 1992 Eur. J Biochem 207 (2) 703-8) as well as by genetic studies in S.cerevisiae where a definitive experiment demonstrated that the Galpha subunit remains associated with the beta/gamma subunits throughout the pheromone signaling event (Klein, Reuveni and Levitzki 2000PNAS 97(7) 3219-23). The dogma is indeed shifting to the Levitzki model as presented since 1984, where recent biophysical methods (like FRET) support the work of the Levitzki claiming that Gs, Gi and Gyeast dissociation is not part of their action. This is already manifested in a few new textbooks like Signal Transduction by B Gompers(2009).
1982-1986-The first group to develop methodologies to reconstitute the eta-receptor-Gs protein-cyclase. To this date this is the only G protein receptor system to be reconstituted from its purified and separate components. This system reaffirmed the validity of the mode of “collision coupling” between the receptor and the Gs protein activated adenylyl cyclase. This collaborative study with Ernst Helmreich and the late Thomas Pfeuffer is a hallmark in the field of receptor biochemistry (Hekman et al.1984 EMBO J 3(13) 3339-45;Feder et al. 1986 EMBO J 5(7) 1507-14).
1987-2000-Signal transduction to Ras and by G proteins in yeast
Using biochemistry, genetics and molecular biology Levitzki studied with high degree of success signal transduction pathways in S.cerevisiae aimed to resolve two general issues in signal transduction. One was the identification of the evolutionary conserved domain in Ras that interacts with its GDP/GTP exchanger Cdc25  (Segal et al 1993 PNAS 90 (12) 5564-8;Segal et al. 1995 Eur J Biochem 228(1) 96-101). Using genetics and biochemical techniques Levitzki identified Cdc25 as the regulator of S.cerevisiae adenylyl cyclase (Daniel et al 1987 MCB 7 (10) 3857-61). Levitzki was also the first to demonstrate that the activity of Cdc25 is attenuated by phosphorylation (Gross et al 1992 Nature 360 (6406) 762-5). This was found as a general mechanism of regulation for Ras exchangers mCdc25 and mSos. By using anti-Cdc25 identified for the first time its mammalian Cdc 25 homolog (Gross et al 1992 MCB 12(6)2653-61) and by genetic/biochemical complementation the C.albicans homolog. The second general problem utilized the pheromone pathway. Levitzki cloned the first signaling scaffold protein Ste5 (Perlman et al. 1993 PNAS 90(12) 5474-8) and showing that it needs to dimerize in order to allow pheromone signaling (Yablonski, Marbach and Levitzki1996 PNAS 93(24),13864-9). The yeast system allowed Levitzki to establish by a molecular biological/biochemical   approach that pheromone signaling through its G protein does not require subunit dissociation. This significant finding establishes that G protein action, does not necessarily involve alpha to beta-gamma dissociation. At least this is true for Gs, Gi and Gyeast (see above).
Levitzki published many invited reviews on the subject of receptors, receptor effector coupling and receptor adenylyl cyclase interactions. He also published a widely read book (1984) on the quantitative aspects of receptor studies, soon to be reissued as an e-book. Like in the case of the book on allosteria, this is still a basic book that is handy to all who want to have a flavor of the quantitative aspects of receptor biology.
1985 onward : signal transduction therapy, protein tyrosine kinase signaling and the development of tyrphostins
One can view Levitzki’s work on regulatory enzymes , receptor biology and mechanism of signal transduction as the ground work for the current activities of Levitzki , namely utilizing the knowledge on signal transduction to develop targeted therapies , based on that knowledge.
           Since 1985 Levitzki has been developing the approach of “signal transduction therapy”, a term he coined in 1994 (Levitzki 1994 Eur J Biochem (1): p. 1-13) . When Levitzki started his work in the mid-1980s on the development of selective small molecule inhibitors of tyrosine kinases, the prevailing view was that although tyrosine kinases are desirable drug targets, the high conservation of the active site of these enzymes makes it unlikely to achieve selectivity and this approach is not likely to succeed. Indeed Quercetin, Genistein and Erbstatin known by 1986 were with poor selectivities and affecting also serine kinases, seemingly supporting that view. Despite these daunting forecasts, Levitzki went ahead, arguing that small differences between the active sites trypsin, chymotrypsin and elastase are sufficient to generate highly selective inhibitors .Levitzki indeed went ahead and demonstrated in two seminal papers in 1988 (Yaish et al. Science, 1988. 242(4880): p. 933-5) and 1989 (Gazit et al J Med Chem. , 1989. 32(10): p. 2344-52) that one can generate cell permeable selective substrate competitive EGFR kinase inhibitors that are more than 1,000-fold less active against insulin receptor kinase, with no measurable affinity towards Ser/Thr kinases. These compounds were found to inhibit EGFR driven signal transduction, cell growth in vitro and in vivo. In 1991-1993(Gazit et al. J Med Chem, 1991. 34(6): p. 1896-907:Gazit et al. J Med Chem, 1993. 36(23): p. 3556-64; Osherov et al. J Biol Chem, 1993. 268(15): p. 11134-42) . His 1991-1993 papers showed, convincingly, for the first time, that ATP competitive inhibitors discriminate between highly related kinases such as EGFR and Her-2 and completely changed the dogma, quickly becoming common knowledge. The 1993 JBC paper was haled by Edwin Krebs (Nobel Prize 1992), then a senior editor of JBC. Furthermore, in 1994 he reported on another highly potent class of ATP competitive inhibitors (Quinoxalines) that block selectively the PDGFR and its signaling (Kovalenko et al. Cancer Res, 1994. 54(23): p. 6106-14).
           These milestone publications convinced researchers in industry and academia to go ahead and generate selective ATP competitive inhibitors against various tyrosine kinases. At present more than a 15 such inhibitors are either in the clinic or at various stages of development (Levitzki 2013 Ann Rev Pharmacol.Toxicol 53, 161-85). Levitzki himself, has been pursuing both ATP- mimics as well substrate-mimics and allosteric kinase inhibitors as his extensive list of publication attests. He has been advocating for a long time substrate competitive inhibitors, which he argues are less toxic but more difficult to make. This is so since the ATP sub-site is more “closed” whereas the substrate site is more “open” and difficult to use for drug design. Indeed, more recent kinase inhibitors explore areas outside the ATP binding domain.
Levitzki coined the term Tyrphostins (Science 1988) to the whole class of tyrosine phosphorylation inhibitors, referred to as such in many publication keywords (>2,900 in PubMed). Cellular activity and anti-tumor in vivo activities were already shown in 1991 for EGFR driven tumors (Yoneda et al.1991, Cancer Research 51(16) 4430-5) and in 1996 for Jak-2 driven acute lymphoblastic leukemia (ALL)(Meydan et al.1996 Nature 379 (6566) 645-8), both the first demonstration of the in vivo efficacy of tyrphostins. Many other publications coming from Levitzki’s laboratory, collaborating laboratories as well as independent laboratories utilizing his tyrphostins demonstrated in vivo activity with acceptable toxicities (see his list of publication).
Levitzki’s work also established the basis for screening for kinase inhibitors , using tyrosine containing polymers as substrates (Levitzki 1991 Methods in Enzymology 201 347-61).The methodology described is the basis of all screening done performed by academic as well as by industrial laboratories.
Most importantly, Levitzki was also the first to develop selective Bcr-Abl kinase inhibitors, some ATP competitive and some substrate competitive (1992 Anafi et al.1992 JBC 267 (7) 4518-23), Anafi et al 1993 Blood 82(12) 3524-9). These compounds induce apoptosis in K562 and inspired the original Gleevec paper by Druker et al (1996), which led to the much celebrated success in the treatment of CML, as fully predicted by Levitzki’s pioneering studies in 1992-3. Druker and his colleagues indeed suggest in their classic 1996 Nature Medicine paper that they follow the work of the Levitzki group. The development of Gleevec is the first proof of principle, in humans, of the Levitzki concept. Daniel Vasella, CEO of Novartis (the developer of Gleevec) at that time, clearly credits Levitzki in the book “Magic Cancer Bullet”, (2003) he authored:
Late in 1988 something happened that would change Brian Druker’s thinking. It was then that a group in Jerusalem headed by Professor Alexander Levitzki published an article in Science magazine suggesting that they have been able to selectively inhibit an Epdermal Growth Factor Receptor…..Levitzki’s article cast kinase inhibitors in a whole new light for Brian Druker. If it was possible to get some specificity (as Levitzki and his group had done with EGF), that meant one could now think seriously about creating an effective compound that would inhibit a specific kinase”. Being the CEO, Daniel Vasella pushed hard the Gleevec project at Novartis. Interestingly, Gleevec was originally developed to inhibit PDGFR and therefore it inhibits both Bcr-Abl, PDGFR and Kit. Levitzki who also recognized early the potential of PDGFR kinase inhibitors for the treatment of cancer (1994, see above) and restenosis (1998 Banai et al Circulation, 1998. 97(19)1960-9; Banai et al. 2004 Cardiovasc Res, 64(1) 165-71) These PDGFR kinase inhibitors (quinoxalines) do not inhibit Bcr-Abl, unlike Gleevec.
Levitzki is also a pioneer in developing VEGFR kinase inhibitors, with Axel Ullrich, for the inhibition of angiogenesis and published with Sugen scientists (Strawn et al. 1996 Cancer Res 56(15) 3540-5) proving for the first time the feasibility of the approach. All the compounds used in that pioneering study were generated in Levitzki’s laboratory and transferred to Sugen.These studies led Sugen (as well as other companies) to go ahead and develop VEGFR kinase inhibitors for the treatment of various cancers. These VEGFR kinase inhibitors reached various stages of clinical and pre-clinical development.  One of them SU 111248/Sutent/Sunitinib, which inhibits VEGFR2 as well as PDGFR has been approved for clinical use. It is actually the direct result of the effort of Levitzki with Sugen scientists.
Levitzki was also the first to develop an allosteric IGF1R kinase inhibitor that is now in development by TyrNovo. This class of novel tyrphostins (NT) induces the dissociation of IGF1R from IRS proteins but does not inhibit not IGF1R auto-phosphorylation. Dissociation of IRS enables the effective binding of Grb2 to the autophosphorylated IGF1R receotor, leading to the activation of the Sos-Ras-Erk pathway, followed by the Serine phosphorylation of IRS protein, inhibiting its tyrosine phosphorylation by the IGF1R , leading to its proteolytic degradation. This first-in-class inhibitor (Reuveni et al 2013 Cancer Research 73(14) 4383-94) leads to strong anti tumor activity : Plexxicon resistant metastatic melanoma (2013) and prostate cancer (2014, Cox et al.Mol Cancer Ther. 2014 Sep 29. pii: molcanther.0842.2013. [Epub ahead of print])  in animal models as well many other cancer cell lines. NT157 and a close analog (NT219) are now in advanced pre-clinical development by TyrNovo of Herzelia (2013). These compounds were licensed from the Levitzki laboratory and NovoTyr. Between 2005 and 2013 they were developed by NovoTyr, founded by Levitzki himself .
Levitzki and colleagues was also the first to demonstrate the synergy between an EGFR kinase inhibitor (tyrphostin RG 13022) with an EGFR directed antibody (mAb108) in inhibiting EGFR over-expressing tumors in vivo (1991 Yoneda et al.Cancer Research51(16) 4430-5). Such combinations are utilized in the clinic. Similarly, Levitzki was the first to point out that PTK inhibitors (typhostins) must be used in “smart cocktails” (1992 Levitzki Faseb J 6(14) 3275-82), as he showed in a 1996 study where he demonstrated the synergy between the AG825, the first Her2 kinase inhibitor, with cytotoxic agents (1996 Tsai et al. Cancer Research 56(5) 1068-74) In this study Levitzki collaborated with scientists-clinicians who had access to cells from patients, with different levels of Her-2 expression. The higher the expression, the higher the synergy observed. In that study Levitzki was actually the first (1996) to prove that tyrphostins can be sensitizers of tumor cells to pro-apoptotic agents and thus use them in combination, inducing cancer cell death. He showed with his Taiwanese collaborators that the level of synergy between a Her-2/neu directed tyrphostin and Cis-platin, doxorubicin or Etoposide is proportional to the degree of Her-2 expression in lung cancer cell lines derived from NSCLC patients from a Taipie’s hospital, which treats the largest number of non-small-cell-lung cancer patients in Taiwan. For his seminal collaboration with Tsai et al. he was honored to (keynote) lecture about his pioneering studies to the Chinese Society of Clinical Oncology in 1996. Today, the idea to combine signal transduction inhibitors that block survival signals with pro-apoptotic agents is pursued by many clinicians and cancer researchers. This work led the Ludwig Institute for cancer research (LICR) to collaborate with Levitzki’s group and develop a combination of the EGFR kinase inhibitor AG 1478 developed in Levitzki’s laboratory (1994 Osherov and Levitzki Eur. J Biochem 225 (3) 1047-53),with cis-platin to treat glioblastoma multiforme , GBM (2001 Nagane et al.J.Neurosurg 95(3) 472-9).
The work of Levitzki on kinase inhibitors is based on solid enzymology of tyrosine kinases and detailed kinetic analysis on the mode of interaction of tyrphostins with their targets . He explored in detail the kinetics of the EGFR phosphorylation reaction and the mode of the EGFR kinase interaction with inhibitors, showing very convincingly that ATP competitive inhibitors, substrate competitive inhibitors and inhibitors that interact with both the ATP binding domain and the substrate binding domain can be highly selective (1992 Posner et al JBC267 (29) 20638-47;1994 Posner et al. Mol.Pharmacol 45 (4) 673-83). He conducted similar work on selective PDGFR kinase inhibitors and demonstrated that the receptor in its pre-activated form reacts differently with the inhibitor as compared to the fully activated (Kovalenko et al. 1997 Biochemistry 36(21) 6260-9), autophosphorylated receptor, thus explaining the details of these highly selective inhibitors .
Levitzki also recognized the potential of these compounds to treat proliferative conditions such as Psoriasis, restenosis as well as other pathologies as can be seen in his own publications and publications from many other laboratories.
The Levitzki group is recognized as the first to realize and implement the immense potential of blocking signal transduction pathways as a therapeutic regimen for disease management and proved the hypothesis set in 1987/8. Levitzki’s group recognized early the wide application of such agents, developed many hundreds of inhibitors, aimed at different tyrosine kinases and demonstrated their efficacy in cellular systems, in cell-free systems and in vivo as can be seen from his extensive list of publications. He also has been developing EGFR kinase inhibitors for PET imaging, and has pioneered the development of substrate competitive Akt/PKB inhibitors.
Levitzki has published extensively also on the utilization of tyrphostins in the dissection of signal transduction pathways. These were used to dissect Insulin signaling (Shechter et al 1989 EMBO J 8(6) 1671-6;) , the activation of PLCgamma by EGFR (Margolis et al1989 Cell57(7) 1101-7) and PLCgamma activation during B cell activation Padeh et al 1991 JCI 87(3) 1114-8) as well as in many subsequent papers Levitzki himself published. More than 3,000 papers in PubMed mention tyrphostin by name, many others mention specific tyrphostins in key words and many more utilize them without citing the source.
          Many investigators around the world have been utilizing many tyrphostins (sold by numerous companies) for studies of signal transduction, for many years now, following Levitzki’s publications. SUGEN. Inc.(California) was founded on Levitzki’s concepts in 1992 and asked Levitzki to help establish its research efforts. He spent a sabbatical year there as their first VP Research and continued to collaborate with them until they were acquired by Pharmacia in 1998. Levitzki also founded NovoTyr in 2005 to develop the NT compounds targeting IGF1R signaling (see above). In 2013 the development was transferred to TyrNovo that is now in very advanced development of NT219. NT219 as well as its analog NT157 were shown to be actually dual signaling inhibtors: targeting the IGF1/IRS as well as inducing the dephosphorylation of PY(705)Stat3 (Flashner-Abramson et al., Oncogene 35, 390,2016). As such this first-in-class inhibitor targets not only the tumor but also the also the tumor supporting microenvironment (Sanchez-Lopez et al.Oncogene, 35,2634, 2016).
Over the years Levitzki has published (and obtained) many patents concerning the utilization of tyrosine kinase inhibitors as anti-cancer agents and as agents to combat psoriasis, Papilloma, restenosis and inflammatory conditions.
         It should be noted that the developments made in Levitzki’s laboratory established the thrust of pharmaceutical companies in the direction of targeting PTKs with small molecules. This started to happen in the early 1990s, after Levitzki’s group set the stage. Understandably, companies dislike to acknowledge originality elsewhere where Vasella’s acknowledgement is freshening. Clearly, between 1988 and 1994, before companies started to work on tyrosine kinase inhibitors, Levitzki was already at the forefront and the most influential leader in this field. This is supported by the invitation by Science to write a review on “ Tyrosine kinase inhibition: an approach to drug development” (Science 1995, March 24 267 a782-8). This is on top of many reviews he was asked to write prior to 1995 and after. Today he is one of many in a field he actually created, but still contributing novel ideas as well as compounds.
Targeting long chain dsRNA to tumors
Since 2005 and in parallel to the development of small signal transduction inhibitory molecules, Levitzki is developing a new strategy to treat cancer by activating the dsRNA (long) response selectively in tumor cells by targeting of PolyIC. The chemical vector carrying PolyIC, is guided by a ligand to a receptor, which is overexpressed on the tumor cell, internalizing the PolyIC loaded vector. The internalized PolyIC induces the production of interferon alpha or beta as well as other cytokines that recruit the innate immune system. These elements cause the demise of all tumor cells, including the ones that do not overexpress the receptor, due to the impressive bystander effect induced by PolyIC. So far Levitzki has demonstrated the feasibility to treat EGFR overexpressing cancer (2006 Shir et al. PloS Med 3(1) pe6; 2011 Shir et al Clin.Cancer Res 17(5) 1033-43). By generating a vector that can be tethered to any ligand (2014 Joubran et al Bioconj.Chem 25(9) 1644-54), Levitzki and his team already generated a Her2 homing vector (Joubran et al. 2014 and Zigler et al.,Canc.Immunol.Res. 4,688, 2016) as well as a PSMA homing vector (submitted). Both, when armed with PolyIC induce the selective killing of breast cancer tumors overexpressing Her2 and metastatic prostate cancer that overexpress PSMA (in progress).
This platform is a unique form of targeting the immune system to the tumor (2013 Zigler et al Curr.Opin.Pharmacol 13(4) 504-510.

2016

[391] Targeting colorectal cancer via its microenvironment by inhibiting IGF-1 receptor-insulin receptor substrate and STAT3 signaling. Sanchez-Lopez E, Flashner-Abramson E, Shalapour S, Zhong Z, Taniguchi, Levitzki A, Karin M.Oncogene. 2016 May 19; 35(20):2634-44.

[392] HER2-Targeted Polyinosine/Polycytosine Therapy Inhibits Tumor Growth and Modulates the Tumor Immune Microenvironment. Zigler M, Shir A, Joubran S, Sagalov A, Klein S, Edinger N, Lau J, Yu SF, Mizraji G, Globerson Levin A, Sliwkowski MX, Levitzki A. Cancer Immunol Res. 2016 Aug; 4(8):688-97.

[393] Targeting polyIC to EGFR over-expressing cells using a dsRNA binding protein domain tethered to EGF. Edinger N, Lebendiker M, Klein S, Zigler M,Langut Y and Levitzki A PloS One, Sep 6;11(9)e0162321doi:10.1371/journal.pone.0162321.

[394] S101, an inhibitor of proliferating T cells, rescues mice from superantigen-induced shock Shir A, Sagiv-Barfi I , Klein S, Geiger T, Zigler M and Levitzki A Submitted.

[395] Engineered protein chimera homes synthetic dsRNA to PSMA, leading to prostate cancer cell death and immune system activation. Langut Y,Edinger N, Flashner-Abramson E,Melamed-Book N, Lebendiker M, Klein S and Levitzki A
Oncotarget, inpress

[396] Targeted Prostate Cancer Therapy Using a PSMA Inhibitor as a Homing Ligand Langut Y,Shir A,Klein s and Levitzki A Submitted.

2014

[385]    The tyrphostin, NT157, suppresses insulin receptor substrates and augments therapeutic response of prostate cancer Naokazu Ibuki N , Ghaffari M Azuma H, Martin E. Gleave, ME, Levitzki A and Cox ME Mol.Cancer.Ther, in press.

[386]    Trageting EGFR and Her-2 overexpressing tumors with EGFR and Her-2 guided affibody carrying vectors Joubran S, Zigler M and Levitzki A Submitted

[387]    The purification of biologically active dsRBD (PKR)-EGF chimera Edinger N, Lebendiker M, Klein S and Levitzki A , Submitted.

[388]    Targeting metastatic prostate cancer by PolyIC bound recombinant vector homing to PSMA Langut, Y, Lebendiker, M and Levitzki A Submitted

[389]    Optimization of the liganded polyethyleneimine polyethylaneglycol vector for nucleic acid delivery Joubran, S, Zigler, M and Levitzki, A submitted

[390]    Targeting IGF1R, Stat3 and angiogenesis pathways with one multi-targeted low molecular weight drug Flashner E,Bar-Eli, M, Klein S and Levitzki A In preparation

2013

[381] Tyrosine kinase inhibitors: views of selectivity, sensitivity, and clinical performance. Levitzki A.Annu Rev Pharmacol Toxicol. 2013;53:161-85. Epub 2012 Oct 8.

[382] Therapeutic destruction of insulin receptor substrates for cancer treatment Reuveni,H.,Flashner, E.,Steiner,L.,Makedonski,K.,Shir,A. and Levitzki, A., Cancer Research. 2013 Jul15 73(14):4383-94,May 7. [Epub ahead of print]

[383] Heterogeneity of gene expression in murine squamous cell carcinoma development- the same tumor by different means Cohen N, Kravchenko-Balasha N , Klein S and Levitzki A PloS One 2013. 8(3):e57748. Epub 2013 Mar 18.

[384] Targeted cancer immune therapy Zigler M, Shir A and Levitzki A Current Opin.Pharmacol. 2013, Aug 13(4) 504-510. May 3[Epub ahead of print]

2012

[378] EGFR-targeted Poly Inosine/Cytosine GE11 Polyplex Leads to Tumor Inhibition of EGFR Over-Expressing Tumors Abourbeh,G.,Shir,A.,Mishani,E.,Ogris,M., Rödl, W. Wagner, E. and Levitzki, A. IUBMB Life.2012, 64, 324-330.

[379] Targeting the immune system to cancer using chemical Receptor Homing Vectors Carrying Poly Inosine/Cytosine (PolyIC) Levitzki A. Frontiers in Oncology . 2012;2:4 .Epub 2012 Feb 8

[380] On a fundamental structure of gene networks in living cells. Kravchenko-Balasha N, Levitzki A, Goldstein A, Rotter V, Gross A, Remacle F, Levine RD. Proc Natl Acad Sci U S A. 2012 Mar 20;109(12): Epub 2012 Mar 5.

2011

[369] Mizrachy-Schwartz, S., Cohen, N., Klein, S., Kravchenko-Balasha, N., Levitzki, A. Up-regulation of AMPK in cancer is mediated through c-Src activation. JBC Published on line, Jan 18, 2011.

[370] Convergence of logic of cellular regulation in different premalignant cells by an information theoretic approach. Kravchenko-Balasha N, Remacle F, Gross A, Rotter V, Levitzki A, Levine RD. BMC Syst Biol. Mar 16, 2011.

[371] Kravchenko-Balasha N, Klein S, Safrai M, Levitzki A. Contribution of gross chromosomal changes to HPV16-induced transformation. Mol Biosyst. 2011 May;7(5):1501-11. Epub 2011 Feb 24. Fertil Steril. 2011 May;95(6):2080-6. Epub 2011 Feb 26.

[372] Microwave-assisted solid-phase aza-peptide synthesis: aza scan of a PKB/Akt inhibitor using aza-arginine and aza-proline precursors. Freeman NS, Tal-Gan Y, Klein S, Levitzki A, Gilon C. J Org Chem. 2011 May 6;76(9):3078-85. Epub 2011 Apr 5.

[373] Nucleic Acid-Based Therapeutics For Glioblastoma. Shir A, Levitzki A, Wagner E, Ogris M. Anticancer Agents Med Chem. 2011 Jun 27. [Epub ahead of print]

[374] Backbone cyclic peptide inhibitors of protein kinase B (PKB/Akt). Tal-Gan Y, Hurevich M, Klein S, Ben-Shimon A, Rosenthal D, Hazan C, Shalev DE, Niv MY, Levitzki A, Gilon C. J Med Chem. 2011 Jul 28;54(14):5154-64. Epub 2011 Jun 22.

[375] Metabolic Stability of Peptidomimetics: N-Methyl and Aza Heptapeptide Analogs of a PKB/Akt Inhibitor. Tal-Gan Y, Freeman NS, Klein S, Levitzki A, Gilon C. Chem Biol Drug Des. 2011 Nov;78(5):887-92. doi: 10.1111/j.1747-0285.2011.01207.x. Epub 2011 Sep 26.

[376] A novel small molecule deubiquitinase inhibitor blocks Jak2 signaling through Jak2 ubiquitination. Kapuria V, Levitzki A, Bornmann WG, Maxwell D, Priebe W, Sorenson RJ, Showalter HD, Talpaz M, Donato NJ. Cell Signal. 201, 23(12): 2076-85. Epub 2011 Aug 9

[377] Tyrphostin-like compounds with ubiquitin modulatory activity as possible therapeutic agents for multiple myeloma Peng,Z.,Pal,A.,Han,D.,Wang,S.,Maxwell,D.,Levitzki,A.,Talpaz,M.,Donato,N., Bornman,W Bio-Organic Medicinal Chemistry.2012. 19(23) 7194-7204.

2010

[360] Hurevich, M., Y. Tal-Gan, et al.,2010. Novel method for the synthesis of urea backbone cyclic peptides using new Alloc-protected glycine building units. J Pept Sci, 2010. 16(4): 178-85.

[361] Levitzki, A. and S. Klein. Signal transduction therapy of cancer. Mol Aspects Med, 2010. (4):287-329.

[362] Remacle, F., N. Kravchenko-Balasha, et al. Information-theoretic analysis of phenotype changes in early stages of carcinogenesis. Proc Natl Acad Sci U S A, 2010. 107(22):10324-9.

[363] Sagiv-Barfi, I., Weiss, E., Levitzki, A. Design, synthesis, and evaluation of quinazoline T cell proliferation inhibitors. Bioorg Med Chem, 2010. 18(17):6404-13.

[364] Tal-Gan, Y., N. S. Freeman, S. Klein, A. Levitzki and C. Gilon,2010. Synthesis and structure-activity relationship studies of peptidomimetic PKB/Akt inhibitors: the significance of backbone interactions. Bioorg Med Chem 18(8): 2976-85.

[365] Schaffert, D., Kiss,M., Rödl, W., Shir, A., Levitzki, A., Ogris, M.,Wagner, E. Poly(I:C) mediated tumor growth suppression in EGF-receptor overexpressing tumors using EGF-polyethylene glycol-linear polyethylenimine as carrier. Pharmaceutical Research 2011,28(4):731-41.

[366] Mizrachy-Schwartz, S., Cohen, N., Klein, S., Kravchenko-Balasha, N., Levitzki, A. Amino acid starvation sensitizes cancer cells to proteasome inhibition. IUBMB Life. 2010 ;62(10):757-63.

[367] Zenvirt, S., Kravchenko-Balasha, N., Levitzki, A. Status of p53 in human cancer cells does not predict efficacy of CHK1 kinase inhibitors combined with chemotherapeutic agents. Oncogene. 2010 Nov 18;29(46):6149-59. Epub 2010 Aug 23.

[368] Shir, A., Ogris, M., Roedl, W., Wagner, E., Levitzki, A. EGFR-homing dsRNA synergizes with the host immune system eliminating EGFR overexpressing tumors. Clinical Cancer Research 2011 Mar 1;17(5):1033-43. Epub 2010 Dec 30..

2009

[356] Klein, S. and A. Levitzki. Targeting the EGFR and the PKB pathway in cancer. Curr Opin Cell Biol, 2009. 21(2): 185-9

[357] Kravchenko-Balasha, N., S. Mizrachy-Schwartz, et al. Shift from apoptotic to necrotic cell death during human papillomavirus-induced transformation of keratinocytes. J Biol Chem, 2009. 284(17): 11717-27.

[358] Reiss-Sklan, E., A. Levitzki, et al. The complex regulation of HIC (Human I-mfa domain containing protein) expression. PLoS One, 2009. 4(7): e6152.

[359] Sagiv, I., P. Idelevich, et al. A color discriminating broad range cell staining technology for early detection of cell transformation. J Carcinog, 2009. 8: 16.

2008

[355] Geiger, T., H. Sabanay, N. Kravchenko-Balasha, B. Geiger, and A. Levitzki, Anomalous Features of EMT during Keratinocyte Transformation. PLoS ONE, 2008. 3(2): p. e1574.

2007

 

[343] Abourbeh, G., S. Dissoki, O. Jacobson, A. Litchi, R.B. Daniel, D. Laki, A. Levitzki, and E. Mishani, Evaluation of radiolabeled ML04, a putative irreversible inhibitor of epidermal growth factor receptor, as a bioprobe for PET imaging of EGFR-overexpressing tumors. Nucl Med Biol, 2007. 34(1): p. 55-70 PDF
[344] Dissoki, S., Aviv, Y., Laky, D., Abourbeh, G., Levitzki, A. and Mishani, E. (2007). The effect of the [18F]-PEG group on tracer qualification of [4-(phenylamino)-quinazoline-6-YL]-amide moiety--an EGFR putative irreversible inhibitor. Appl Radiat Isot 65(10): 1140-51. PDF
[345] Geiger, T. and A. Levitzki, Loss of Robustness and Addiction to IGF1 during Early Keratinocyte Transformation by Human Papilloma Virus 16. PLoS ONE, 2007. 2: p. e605. PDF
[346] Gus, Y., Karni, R. and Levitzki, A. (2007). Subunit S5a of the 26S proteasome is regulated by antiapoptotic signals. Febs J 274(11): 2815-31. PDF
[347] Klein, S., Levitzki ,A., Targeted Cancer Therapy: Promise and Reality. Adv.Cancer Res, 2007. 97:295. PDF
[348] Hirokawa, Y., A. Levitzki, G. Lessene, J. Baell, Y. Xiao, H. Zhu, and H. Maruta, Signal therapy of human pancreatic cancer and NF1-deficient breast cancer xenograft in mice by a combination of PP1 and GL-2003, anti-PAK1 drugs (Tyr-kinase inhibitors). Cancer Lett, 2007. 245(1-2): p. 242-51. PDF
 [349] Levitzki, A., Signal Transduction Therapy of Cancer from Concept to Clinic:Promises and Hurdles. AACR Centennial, 2007(April 14-18, 2007).  N/A Online
[350] Levitzki, A. (2007). Protein Kinase Inhibitors. Handbook of Cell Signaling.  N/A Online
[351] Litman, P., Ohne, O., Ben-Yaakov, S., Shemesh-Darvish, L., Yechezkel, T., Salitra, Y., Rubnov, S., Cohen, I., Senderowitz, H., Kidron, D., Livnah, O., Levitzki, A. and Livnah, N. (2007). A novel substrate mimetic inhibitor of PKB/Akt inhibits prostate cancer tumor growth in mice by blocking the PKB pathway. Biochemistry 46(16): 4716-24. PDF
[352] Mizrachy-Schwartz, S., N. Kravchenko-Balasha, H. Ben-Bassat, S. Klein, and A. Levitzki,Optimization of Energy-Consuming Pathways towards Rapid Growth in HPV-Transformed Cells. PLoS ONE, 2007. 2: p. e628.  N/A Online
[353] Steiner, L., G. Blum, Y. Friedmann, and A. Levitzki, ATP non-competitive IGF-1 receptor kinase inhibitors as lead anti-neoplastic and anti-papilloma agents. Eur J Pharmacol, 2007. 562(1-2): p. 1-11. PDF
[354] Winograd-Katz, S.E. and A. Levitzki, Cisplatin induces PKB/Akt activation and p38(MAPK) phosphorylation of the EGF receptor. Oncogene, 2007. 26(5): p. 788. PDF
2006
[336] Ellis, A. G., M. M. Doherty, F. Walker, J. Weinstock, M. Nerrie, A. Vitali, R. Murphy, T. G. Johns, A. M. Scott, A. Levitzki, G. McLachlan, L. K. Webster, A. W. Burgess and E. C. Nice (2006).Preclinical analysis of the analinoquinazoline AG1478, a specific small molecule inhibitor of EGF receptor tyrosine kinase. Biochem Pharmacol. 2006 May 14;71(10):1422-34. PDF
[337] Klein, S. and A. Levitzki (2006). Signal Transduction Therapy for Cancer – Whither Now?Current Signal Transduction Therapy 1: 1-12.  N/A Online
[338] Levitzki, A. (2006). Principles of Signal Transduction in Oncology. Signaltransduktion in der Onkologie D.C. Dittrich, Editor.(UNI-MED Verlag AG: Bremen): 16-25.  N/A Online
[339] Levitzki, A. (2006). Chronic myeloid leukemia and Gleevec. Signaltransduktion in der Onkologie, D.C. Dittrich, Editor.(UNI-MED Verlag AG: Bremen): 30-35.   N/A Online
[340] Levitzki, A. and E. Mishani (2006). Tyrphostins and other tyrosine kinase inhibitors. Annu Rev Biochem 75: 93-109. PDF
[341] Shir, A., M. Ogris, E. Wagner and A. Levitzki (2006). EGF receptor-targeted synthetic double-stranded RNA eliminates glioblastoma, breast cancer, and adenocarcinoma tumors in mice. PLoS Med 3(1): e6. PDF
[342] Winograd-Katz, S. E. and A. Levitzki (2006). Cisplatin induces PKB/Akt activation andp38(MAPK) phosphorylation of the EGF receptor. Oncogene 25(56): 7381-90. PDF
2005
[327] Banai, S., Chorny, M., Gertz, S. D., Fishbein, I., Gao, J., Perez, L., Lazarovichi, G., Gazit, A., Levitzki, A., and Golomb, G. (2005). Locally Delivered Nanoencapsulated Tyrphostin (AGL-2043) Reduces Neointima Formation in Balloon-injured Rat Carotid and Stented Porcine Coronary Arteries. Biomaterials 4, 451-61. PDF
[328] Friedrich, I., H. Ben-Bassat and A. Levitzki (2005). Activation of dsRNA dependent protein kinase PKR in Karpas299 does not lead to cell death. Cancer Biol Ther 4(7): 734-9.

 

PDF
[329] Friedrich, I., M. Eizenbach, J. Sajman, H. Ben-Bassat and A. Levitzki (2005). A cellular screening assay to test the ability of PKR to induce cell death in mammalian cells. Mol Ther 12(5): 969-75. PDF
[330] George, J., I. Barshack, P. Keren, A. Gazit, A. Levitzki, G. Keren and A. Roth (2005). The effect of tyrphostin AG-556 on intimal thickening in a mouse model of arterial injury. Exp Mol Pathol 78(3): 233-8. PDF
[331] Karni, R., Y. Gus, Y. Dor, O. Meyuhas and A. Levitzki (2005). Active Src elevates the expression of beta-catenin by enhancement of cap-dependent translation. Mol Cell Biol 25(12): 5031-9. PDF
[332] Klein S., Geiger T., Linchevski I., Lebendiker M., Itkin A., Assayag K., Levitzki A. (2005).Expression and purification of active PKB kinase from Escherichia coli. . Protein Expression and Purification 41, 162-9. PDF
[333] Klein, S., F. McCormick and A. Levitzki (2005). Killing time for cancer cells. Nat Rev Cancer 5(7): 573-80. PDF
[334] Levitzki A. (2005). PDGF receptor kinase inhibitors for the treatment of restenosis. .Cardiovascular Research 65, 581-6. PDF
[335] Mishani, E., G. Abourbeh, O. Jacobson, S. Dissoki, R. Ben Daniel, Y. Rozen, M. Shaul and A. Levitzki (2005). High-affinity epidermal growth factor receptor (EGFR) irreversible inhibitors with diminished chemical reactivities as positron emission tomography (PET)-imaging agent candidates of EGFR overexpressing tumors.J Med Chem 48(16): 5337-48. PDF
2004
[317] Friedrich I., Shir A., Klein S., Levitzki A. (2004). RNA molecules as anti-cancer agents. Semin Cancer Biol 14, 223-30. PDF
[318] George, J., Barshack, I., Goldberg, I., Keren, P., Gazit, A., Levitzki, A., Keren, G., and Roth, A. (2004). The effect of early and late treatment with the tyrphostin AG-556 on the progression of experimental autoimmune myocarditis. Exp Mol Pathol 76, 234-241. PubMed
[319] He, H., Hirokawa, Y., Gazit, A., Yamashita, Y., Mano, H., Kawakami, Y., Kawakami, Hsieh C.Y., Kung, H.J., Lessene, G., Baell, J., Levitzki, A., Maruta, H.(2004). The Tyr-Kinase Inhibitor AG879, That Blocks the ETK-PAK1 Interaction, Suppresses the RAS-Induced PAK1 Activation and Malignant Transformation. Cancer Biol Ther 3 (1), 96-101. PDF
[320] Levitzki, A., and Klein, S. (2004). From Tyrphostins to Gleevec: Signal Transduction Therapy - From Concept to the Clinic. In Life Sciences for the 21st century, E. Keinan, I. Schechter, and M. Sela, eds., pp. 175-189. N/A Online
[321] Levitzki, A. (2004). PDGF receptor kinase inhibitors for the treatment of PDGF driven diseases. Cytokine Growth Factor Rev. 15, 229-35. PDF
[322] Mishani, E., Abourbeh, G., Rozen, Y., Jacobson, O., Laky, D., Ben David, I., Levitzki, A., and Shaul, M. (2004). Novel carbon-11 labeled 4-dimethylamino-but-2-enoic acid [4-(phenylamino)-quinazoline-6-yl]-amides:potential PET bioprobes for molecular imaging of EGFR-positive tumors. Nucl Med Biology 31, 469-476. PDF
[323] Rayan, A., Noy, E., Chema, D., Levitzki, A., and Goldblum, A. (2004). Stochastic algorithm for kinase homology model construction. Curr Med Chem 11, 675-692. PubMed
[324] Shaul, M., Abourbeh, G., Jacobson, O., Rozen, Y., Laky, D., Levitzki, A., and Mishani, E. (2004). Novel iodine-124 labeled EGFR inhibitors as potential PET agents for molecular imaging in cancer. Bioorg Med Chem 12, 3421-3429. PDF
[325] Levitzki A. (2004). Introduction: Signal transduction therapy-10 years later. Semin Cancer Biol 14, 219-21. PDF
[326] Banai S., Gertz S.D., Gavish L., Chorny M., Perez L.S., Lazarovichi G., Ianculuvich M., Hoffmann M., Orlowski M., Golomb G., Levitzki A. (2004). Tyrphostin AGL-2043 eluting stent reduces neointima formation in porcine coronary arteries. Cardiovasc Res. 2004 Oct 1;64(1):165-71. PDF
2003
[304] Baars, S., Bachmann, A., Levitzki, A. & Rosl, F. (2003). Tyrphostin AG55 inhibits bovine papillomavirus transcription by changing the ratio between E2 transactivator/repressor function. J Biol Chem. 278, 37306-13. PDF
[305] Blum, G., Gazit, A. & Levitzki, A. (2003). Development of new IGF-1 receptor kinase inhibitors using catechol mimics. J Biol Chem. 278, 40442-54. PDF
[306] Gazit, A., Yee, K., Uecker, A., Bohmer, F. D., Sjoblom, T., Ostman, A., Waltenberger, J., Golomb, G., Banai, S., Heinrich, M. C., and Levitzki, A. (2003). Tricyclic quinoxalines as potent kinase inhibitors of PDGFR kinase, Flt3 and Kit. Bioorg Med Chem 11, 2007-18. PDF
[307] George, J., Biner, S., Keren, P., Barshack, I., Goldberg, I., Sherez, J., Levitzki, A., Keren, G., and Roth, A. (2003).Tyrphostin AG-556 reduces myocardial infarct size and improves cardiac performance in the rat. Exp Mol Pathol 74, 314-8. PDF
[308] Karni, R., Mizrachi, S., Reiss-Sklan, E., Gazit, A., Livnah, O., and Levitzki, A. (2003). The pp60c-Src inhibitor PP1 is non-competitive against ATP. FEBS Lett 537, 47-52 PDF
[309] Levitzki, A. (2003). Protein kinase inhibitors as a therapeutic modality. Acc Chem Res 36, 462-9. PDF
[310] Levitzki, A. (2003). EGF receptor as a therapeutic target. Lung Cancer 41 Suppl 1, S9-S14. PDF
[311] Levitzki, A. (2003). Signal Transduction Therapy. In Molecular Pathomechanisms and New Trends in Drug Research, G. Keri and I. Toth, eds. N/A Online
[312] Levitzki, A. (2003). The closure of Sugen. Nat Biotechnol 21, 969. PDF
[313] Levitzki, A. (2003). Protein Kinase Inhibitors. In Handbook of Cell Signaling, Chapter 77, pp. 451-461. N/A Online
[314] Levitzki, A., and Ben-Yehudah, D. (2003). From tyrphostins to Iressa and Gleevec: Signal transduction therapy from concept to the patient bed. In Chemical Probes in Biology, M. P. Schneider, ed., pp. 391-402. N/A Online
[315] Reuveni, H., Klein, S., and Levitzki, A.(2003). The inhibition of Ras farnesylation leads to an increase in p27Kip1 and G1 cell cycle arrest. Eur J Biochem 270, 2759-72 PDF
[316] Shir, A., Friedrich, I., and Levitzki, A. (2003). Tumor specific activation of PKR as a non-toxic modality of cancer treatment. Semin Cancer Biol 13, 309-314. PDF
2002
[291] Ben-Bassat, H., Hartzstark, Z., Levitzki, R., Klein, B. Y., Shlomai, Z., Gazit, A., and Levitzki, A. (2002). Tyrosine kinase inhibitors suppress the growth of non-hodgkin B lymphomas. J Pharmacol Exp Ther 303, 163-71 PDF
[292] Benhar, M., Engelberg, D., and Levitzki, A. (2002). Cisplatin-induced activation of the EGF receptor. Oncogene 21, 8723-31. PDF
[293] Benhar, M., Engelberg, D., and Levitzki, A. (2002). ROS, stress-activated kinases and stress signaling in cancer.EMBO Rep 3, 420-5. PDF
[294] Burdelya, L., Catlett-Falcone, R., Levitzki, A., Cheng, F., Mora, L. B., Sotomayor, E., Coppola, D., Sun, J., Sebti, S., Dalton, W. S., Jove, R., and Yu, H. (2002). Combination therapy with AG-490 and interleukin 12 achieves greater antitumor effects than either agent alone. Mol Cancer Ther 1, 893-9 PDF
[295] Carlomagno, F., Vitagliano, D., Guida, T., Napolitano, M., Vecchio, G., Fusco, A., Gazit, A., Levitzki, A., and Santoro, M. (2002). The kinase inhibitor PP1 blocks tumorigenesis induced by RET oncogenes. Cancer Res 62, 1077-82. PDF
[296] Karck, M., Meliss, R., Hestermann, M., Mengel, M., Pethig, K., Levitzki, A., Banai, S., Golomb, G., Fishbein, I., Chorny, M., and Haverich, A. (2002). Inhibition of aortic allograft vasculopathy by local delivery of platelet-derived growth factor receptor tyrosine-kinase blocker AG-1295. Transplantation 74, 1335-41. PubMed
[297] Karni, R., Dor, Y., Keshet, E., Meyuhas, O., and Levitzki, A. (2002). Activated pp60c-Src leads to elevated hypoxia-inducible factor (HIF)- 1alpha expression under normoxia. J Biol Chem 277, 42919-25. PDF
[298] Levitzki, A. (2002). Tyrosine kinases as targets for cancer therapy. Eur J Cancer 38 Suppl 5, S11-8. PDF
[299] Levitzki, A. (2002). Protein Kinase Inhibitors. In Encyclopedia of Cancer (USA: Elsevier Science), pp. 475-80. PubMed
[300] Levitzki, A., and Klein, S. (2002). G-protein subunit dissociation is not an integral part of G-protein action.Chembiochem 3, 815-8. PDF
[301] Ortu, G., Ben-David, I., Rozen, Y., Freedman, N. M., Chisin, R., Levitzki, A., and Mishani, E. (2002). Labeled EGFr-TK irreversible inhibitor (ML03): in vitro and in vivo properties, potential as PET biomarker for cancer and feasibility as anticancer drug. Int J Cancer 101, 360-70. PDF
[302] Reuveni, H., Livnah, N., Geiger, T., Klein, S., Ohne, O., Cohen, I., Benhar, M., Gellerman, G., and Levitzki, A. (2002).Toward a PKB inhibitor: modification of a selective PKA inhibitor by rational design. Biochemistry 41, 10304-14. PDF
[303] Shir, A., and Levitzki, A. (2002). Inhibition of glioma growth by tumor-specific activation of double- stranded RNA-dependent protein kinase PKR. Nat Biotechnol 20, 895-900. PDF
2001

Demo Content

2000
[267] Ben-Bassat, H., and Levitzki, A. (2000). Inhibitors of tyrosine kinases in the treatment of psoriasis. Isr Med Assoc J 2 Suppl, 69-73. PubMed
[268] Blum, G., Gazit, A., and Levitzki, A. (2000). Substrate competitive inhibitors of IGF-1 receptor kinase. Biochemistry 39, 15705-12. PDF
[269] Fishbein, I., Waltenberger, J., Banai, S., Rabinovich, L., Chorny, M., Levitzki, A., Gazit, A., Huber, R., Mayr, U., Gertz, S. D., and Golomb, G. (2000). Local delivery of platelet-derived growth factor receptor-specific tyrphostin inhibits neointimal formation in rats. Arterioscler Thromb Vasc Biol 20, 667-76. PDF
[270] He, H., Hirokawa, Y., Levitzki, A., and Maruta, H. (2000). An anti-Ras cancer potential of PP1, an inhibitor specific for Src family kinases: in vitro and in vivo studies. Cancer J 6, 243-8. PubMed
[271] Karni, R., and Levitzki, A. (2000). pp60(cSrc) is a caspase-3 substrate and Is essential for the transformed phenotype of A431 cells. Mol Cell Biol Res Commun 3, 98-104. PDF
[272] Klein, S., Reuveni, H., and Levitzki, A. (2000). Signal transduction by a nondissociable heterotrimeric yeast G protein. Proc Natl Acad Sci U S A 97, 3219-23. PDF
[273] Levitzki, A. (2000). Protein tyrosine kinase inhibitors as novel therapeutic agents. In Signaling Networks and Cell Cycle Control: The Molecular Basis of Cancer and Other Diseases, J. S. Gutkind, ed. (Totowa, NJ: Humana Press Inc.), pp. 453-65. N/A Online
[274] Levitzki, A. (2000). Protein tyrosine kinase inhibitors as therapeutic agents. In Topics in Current Chemistry (Berlin Heidelberg: Springer-Verlag), pp. 1-15. N/A Online
[275] Levitzki, A., and Gazit, A. (2000). The Potential of Tyrphostins for the Therapy of Breast Cancer. Breast CancerDisease 11, 145-52. N/A Online
[276] Reuveni, H., Geiger, T., Geiger, B., and Levitzki, A. (2000). Reversal of the Ras-induced transformed phenotype by HR12, a novel ras farnesylation inhibitor, is mediated by the Mek/Erk pathway. J Cell Biol 151, 1179-92. PDF
[277] Volberg, T., Bershadsky, A. D., Elbaum, M., Gazit, A., Levitzki, A., and Geiger, B. (2000). Disruption of microtubules in living cells by tyrphostin AG-1714. Cell Motil Cytoskeleton 45, 223-34. PDF
[278] Zhang, Y., Turkson, J., Carter-Su, C., Smithgall, T., Levitzki, A., Kraker, A., Krolewski, J. J., Medveczky, P., and Jove, R. (2000). Activation of Stat3 in v-Src-transformed fibroblasts requires cooperation of Jak1 kinase activity. J Biol Chem 275, 24935-44. PDF
1999
[257] Ben-Bassat, H., Rosenbaum-Mitrani, S., Hartzstark, Z., Levitzki, R., Chaouat, M., Shlomai, Z., Klein, B. Y., Kleinberger-Doron, N., Gazit, A., Tsvieli, R., and Levitzki, A. (1999). Tyrphostins that suppress the growth of human papilloma virus 16- immortalized human keratinocytes. J Pharmacol Exp Ther 290, 1442-57. PDF
[258] Carlo-Stella, C., Regazzi, E., Sammarelli, G., Colla, S., Garau, D., Gazit, A., Savoldo, B., Cilloni, D., Tabilio, A., Levitzki, A., and Rizzoli, V. (1999). Effects of the tyrosine kinase inhibitor AG957 and an Anti-Fas receptor antibody on CD34(+) chronic myelogenous leukemia progenitor cells. Blood 93, 3973-82. PDF
[259] Catlett-Falcone, R., Landowski, T. H., Oshiro, M. M., Turkson, J., Levitzki, A., Savino, R., Ciliberto, G., Moscinski, L., Fernandez-Luna, J. L., Nunez, G., Dalton, W. S., and Jove, R. (1999). Constitutive activation of Stat3 signaling confers resistance to apoptosis in human U266 myeloma cells. Immunity 10, 105-15. PDF
[260] Gross, A., Winograd, S., Marbach, I., and Levitzki, A. (1999). The N-terminal half of Cdc25 is essential for processing glucose signaling in Saccharomyces cerevisiae. Biochemistry 38, 13252-62. PDF
[261] Karni, R., Jove, R., and Levitzki, A. (1999). Inhibition of pp60c-Src reduces Bcl-XL expression and reverses the transformed phenotype of cells overexpressing EGF and HER-2 receptors. Oncogene 18, 4654-62. PDF
[262] Levitzki, A. (1999). Protein tyrosine kinase inhibitors as novel therapeutic agents. Pharmacol Ther 82, 231-9. PDF
[263] Poradosu, E., Gazit, A., Reuveni, H., and Levitzki, A. (1999). Alpha-cyanocinnamide derivatives: a new family of non-peptide, non- sulfhydryl inhibitors of Ras farnesylation. Bioorg Med Chem 7, 1727-36. PDF
[264] Powell, T. J., Ben-Bassat, H., Klein, B. Y., Chen, H., Shenoy, N., McCollough, J., Narog, B., Gazit, A., Harzstark, Z., Chaouat, M., Levitzki, R., Tang, C., McMahon, J., Shawver, L., and Levitzki, A. (1999). Growth inhibition of psoriatic keratinocytes by quinazoline tyrosine kinase inhibitors. Br J Dermatol 141, 802-10. PDF
[265] Schindler, T., Sicheri, F., Pico, A., Gazit, A., Levitzki, A., and Kuriyan, J. (1999). Crystal structure of Hck in complex with a Src family-selective tyrosine kinase inhibitor. Mol Cell 3, 639-48. PDF
[266] Waltenberger, J., Uecker, A., Kroll, J., Frank, H., Mayr, U., Bjorge, J. D., Fujita, D., Gazit, A., Hombach, V., Levitzki, A., and Bohmer, F. D. (1999). A dual inhibitor of platelet-derived growth factor beta-receptor and Src kinase activity potently interferes with motogenic and mitogenic responses to PDGF in vascular smooth muscle cells. A novel candidate for prevention of vascular remodeling. Circ Res 85, 12-22. PDF
1998
[250] Banai, S., Wolf, Y., Golomb, G., Pearle, A., Waltenberger, J., Fishbein, I., Schneider, A., Gazit, A., Perez, L., Huber, R., Lazarovichi, G., Rabinovich, L., Levitzki, A., and Gertz, S. D. (1998). PDGF-receptor tyrosine kinase blocker AG1295 selectively attenuates smooth muscle cell growth in vitro and reduces neointimal formation after balloon angioplasty in swine. Circulation 97, 1960-9. PDF
[251] Brenner, T., Poradosu, E., Soffer, D., Sicsic, C., Gazit, A., and Levitzki, A. (1998). Suppression of experimental autoimmune encephalomyelitis by tyrphostin AG-556. Exp Neurol 154, 489-98. PDF
[252] Kleinberger-Doron, N., Shelah, N., Capone, R., Gazit, A., and Levitzki, A. (1998). Inhibition of Cdk2 activation by selected tyrphostins causes cell cycle arrest at late G1 and S phase. Exp Cell Res 241, 340-51. PDF
[253] Levitzki, A., and Bohmer, F. D. (1998). Altered efficacy and selectivity of tyrosine kinase inhibitors of the activated states of protein tyrosine kinases. Anticancer Drug Des 13, 731-4. PubMed
[254] Lipson, K. E., Pang, L., Huber, L. J., Chen, H., Tsai, J. M., Hirth, P., Gazit, A., Levitzki, A., and McMahon, G. (1998).Inhibition of platelet-derived growth factor and epidermal growth factor receptor signaling events after treatment of cells with specific synthetic inhibitors of tyrosine kinase phosphorylation. J Pharmacol Exp Ther 285, 844-52. PDF
[255] Nagane, M., Levitzki, A., Gazit, A., Cavenee, W. K., and Huang, H. J. (1998). Drug resistance of human glioblastoma cells conferred by a tumor- specific mutant epidermal growth factor receptor through modulation of Bcl-XL and caspase-3-like proteases. Proc Natl Acad Sci U S A 95, 5724-9. PDF
[256] Walker, F., Kato, A., Gonez, L. J., Hibbs, M. L., Pouliot, N., Levitzki, A., and Burgess, A. W. (1998). Activation of the Ras/mitogen-activated protein kinase pathway by kinase-defective epidermal growth factor receptors results in cell survival but not proliferation. Mol Cell Biol 18, 7192-204. PDF
1997
[239] Ben-Bassat, H., Rosenbaum-Mitrani, S., Hartzstark, Z., Shlomai, Z., Kleinberger-Doron, N., Gazit, A., Plowman, G., Levitzki, R., Tsvieli, R., and Levitzki, A. (1997). Inhibitors of epidermal growth factor receptor kinase and of cyclin- dependent kinase 2 activation induce growth arrest, differentiation, and apoptosis of human papilloma virus 16-immortalized human keratinocytes. Cancer Res 57, 3741-50. PubMed
[240] Kovalenko, M., Ronnstrand, L., Heldin, C. H., Loubtchenkov, M., Gazit, A., Levitzki, A., and Bohmer, F. D. (1997).Phosphorylation site-specific inhibition of platelet-derived growth factor beta-receptor autophosphorylation by the receptor blocking tyrphostin AG1296. Biochemistry 36, 6260-9. PDF
[241] Levitzki, A. (1997). Ligand binding. In Protein Function: a practical approach, T. E. Creighton, ed.: IRL press), pp. 101-29. N/A Online
[242] Levitzki, A. (1997). Targeting signal transduction for disease therapy. Med Oncol 14, 83-9. PubMed
[243] Lopez-Talavera, J. C., Levitzki, A., Martinez, M., Gazit, A., Esteban, R., and Guardia, J. (1997). Tyrosine kinase inhibition ameliorates the hyperdynamic state and decreases nitric oxide production in cirrhotic rats with portal hypertension and ascites. J Clin Invest 100, 664-70. PDF
[244] Osherov, N., and Levitzki, A. (1997). Tyrphostin AG 494 blocks Cdk2 activation. FEBS Lett 410, 187-90. PubMed
[245] Palumbo, G. A., Yarom, N., Gazit, A., Sandalon, Z., Baniyash, M., Kleinberger-Doron, N., Levitzki, A., and Ben-Yehuda, D. (1997). The tryphostin AG17 induces apoptosis and inhibition of cdk2 activity in a lymphoma cell line that overexpresses bcl-2. Cancer Res 57, 2434-9. PubMed
[246] Parrizas, M., Gazit, A., Levitzki, A., Wertheimer, E., and LeRoith, D. (1997). Specific inhibition of insulin-like growth factor-1 and insulin receptor tyrosine kinase activity and biological function by tyrphostins. Endocrinology 138, 1427-33. PDF
[247] Reuveni, H., Gitler, A., Poradosu, E., Gilon, C., and Levitzki, A. (1997). Synthesis and biological activity of semipeptoid farnesyltransferase inhibitors. Bioorg Med Chem 5, 85-92. PDF
[248] Sevransky, J. E., Shaked, G., Novogrodsky, A., Levitzki, A., Gazit, A., Hoffman, A., Elin, R. J., Quezado, Z. M., Freeman, B. D., Eichacker, P. Q., Danner, R. L., Banks, S. M., Bacher, J., Thomas, M. L., 3rd, and Natanson, C. (1997). Tyrphostin AG 556 improves survival and reduces multiorgan failure in canine Escherichia coli peritonitis. J Clin Invest 99, 1966-73. PDF
[249] Wessely, O., Mellitzer, G., von Lindern, M., Levitzki, A., Gazit, A., Ischenko, I., Hayman, M. J., and Beug, H. (1997).Distinct roles of the receptor tyrosine kinases c-ErbB and c-Kit in regulating the balance between erythroid cell proliferation and differentiation. Cell Growth Differ 8, 481-93. PubMed
1996
[227] Fishbein, I., Banai, S., Levitzki, A., Moscovitz, D., Gertz, S. D., Gazit, A., and Golomb, G. (1996). Perivascular and intraluminal delivery systems of a tyrphostin for the treatment of restenosis. Proceed. Intern. Symp. Control. Rel. Bioact. Mater. 23, 17-18. N/A Online
[228] Gazit, A., App, H., McMahon, G., Chen, J., Levitzki, A., and Bohmer, F. D. (1996). Tyrphostins. 5. Potent inhibitors of platelet-derived growth factor receptor tyrosine kinase: structure-activity relationships in quinoxalines, quinolines, and indole tyrphostins. J Med Chem 39, 2170-7. PDF
[229] Gazit, A., Chen, J., App, H., McMahon, G., Hirth, P., Chen, I., and Levitzki, A. (1996). Tyrphostins IV--highly potent inhibitors of EGF receptor kinase. Structure-activity relationship study of 4-anilidoquinazolines. Bioorg Med Chem 4, 1203-7. PDF
[230] Gazit, A., Osherov, N., Gilon, C., and Levitzki, A. (1996). Tyrphostins. 6. Dimeric benzylidenemalononitrile tyrophostins: potent inhibitors of EGF receptor tyrosine kinase in vitro. J Med Chem 39, 4905-11. PDF
[231] Golomb, G., Fishbein, I., Banai, S., Mishaly, D., Moscovitz, D., Gertz, S. D., Gazit, A., Poradosu, E., and Levitzki, A. (1996). Controlled delivery of a tyrphostin inhibits intimal hyperplasia in a rat carotid artery injury model.Atherosclerosis 125, 171-82. PDF
[232] Levitzki, A. (1996). SRC as a target for anti-cancer drugs. Anticancer Drug Des 11, 175-82. PDF
[233] Levitzki, A. (1996). Targeting signal transduction for disease therapy. Curr Opin Cell Biol 8, 239-44. PubMed
[234] Meydan, N., Grunberger, T., Dadi, H., Shahar, M., Arpaia, E., Lapidot, Z., Leeder, J. S., Freedman, M., Cohen, A., Gazit, A., Levitzki, A., and Roifman, C. M. (1996). Inhibition of acute lymphoblastic leukaemia by a Jak-2 inhibitor. Nature 379, 645-8. PubMed
[235] Strawn, L. M., McMahon, G., App, H., Schreck, R., Kuchler, W. R., Longhi, M. P., Hui, T. H., Tang, C., Levitzki, A., Gazit, A., Chen, I., Keri, G., Orfi, L., Risau, W., Flamme, I., Ullrich, A., Hirth, K. P., and Shawver, L. K. (1996). Flk-1 as a target for tumor growth inhibition. Cancer Res 56, 3540-5. PubMed
[236] Tsai, C. M., Levitzki, A., Wu, L. H., Chang, K. T., Cheng, C. C., Gazit, A., and Perng, R. P. (1996). Enhancement of chemosensitivity by tyrphostin AG825 in high-p185(neu) expressing non-small cell lung cancer cells. Cancer Res 56, 1068-74. PubMed
[237] Vanichkin, A., Patya, M., Gazit, A., Levitzki, A., and Novogrodsky, A. (1996). Late administration of a lipophilic tyrosine kinase inhibitor prevents lipopolysaccharide and Escherichia coli-induced lethal toxicity. J Infect Dis 173, 927-33. PubMed
[238] Yablonski, D., Marbach, I., and Levitzki, A. (1996). Dimerization of Ste5, a mitogen-activated protein kinase cascade scaffold protein, is required for signal transduction. Proc Natl Acad Sci U S A 93, 13864-9. PDF
1995
[221] Ben-Bassat, H., Vardi, D. V., Gazit, A., Klaus, S. N., Chaouat, M., Hartzstark, Z., and Levitzki, A. (1995). Tyrphostins suppress the growth of psoriatic keratinocytes. Exp Dermatol 4, 82-8. PubMed
[222] Hurwitz, N., Segal, M., Marbach, I., and Levitzki, A. (1995). Differential activation of yeast adenylyl cyclase by Ras1 and Ras2 depends on the conserved N terminus. Proc Natl Acad Sci U S A 92, 11009-13. PDF
[223] Levitzki, A. (1995). Signal transduction interception as a novel approach to disease management. Ann N Y Acad Sci 766, 363-8. PubMed
[224] Levitzki, A., and Gazit, A. (1995). Tyrosine kinase inhibition: an approach to drug development. Science 267, 1782-8. PubMed
[225] Mazumder, A., Gazit, A., Levitzki, A., Nicklaus, M., Yung, J., Kohlhagen, G., and Pommier, Y. (1995). Effects of tyrphostins, protein kinase inhibitors, on human immunodeficiency virus type 1 integrase. Biochemistry 34, 15111-22. PubMed
[226] Segal, M., Marbach, I., Willumsen, B. M., and Levitzki, A. (1995). Two distinct regions of Ras participate in functional interaction with GDP-GTP exchangers. Eur J Biochem 228, 96-101. PubMed
1994
[210] Agbotounou, W. K., Levitzki, A., Jacquemin-Sablon, A., and Pierre, J. (1994). Effects of tyrphostins on the activated c-src protein in NIH/3T3 cells. Mol Pharmacol 45, 922-31. PubMed
[211] Goldberg, D., Segal, M., and Levitzki, A. (1994). Cdc25 is not the signal receiver for glucose induced cAMP response in S. cerevisiae. FEBS Lett 356, 249-54. PubMed
[212] Kaur, G., Gazit, A., Levitzki, A., Stowe, E., Cooney, D. A., and Sausville, E. A. (1994). Tyrphostin induced growth inhibition: correlation with effect on p210bcr-abl autokinase activity in K562 chronic myelogenous leukemia. Anticancer Drugs 5, 213-22. PubMed
[213] Kovalenko, M., Gazit, A., Bohmer, A., Rorsman, C., Ronnstrand, L., Heldin, C. H., Waltenberger, J., Bohmer, F. D., and Levitzki, A. (1994). Selective platelet-derived growth factor receptor kinase blockers reverse sis-transformation. Cancer Res 54, 6106-14. PubMed
[214] Levitzki, A. (1994). Protein Tyrosine Kinase Inhibitors. In New Molecular Targets for Cancer Chemotherapy: Kerr & Workman). N/A Online
[215] Levitzki, A. (1994). Signal-transduction therapy. A novel approach to disease management. Eur J Biochem 226, 1-13. PubMed
[216] Markovits, J., Larsen, A. K., Segal-Bendirdjian, E., Fosse, P., Saucier, J. M., Gazit, A., Levitzki, A., Umezawa, K., and Jacquemin-Sablon, A. (1994). Inhibition of DNA topoisomerases I and II and induction of apoptosis by erbstatin and tyrphostin derivatives. Biochem Pharmacol 48, 549-60. PubMed
[217] Novogrodsky, A., Vanichkin, A., Patya, M., Gazit, A., Osherov, N., and Levitzki, A. (1994). Prevention of lipopolysaccharide-induced lethal toxicity by tyrosine kinase inhibitors. Science 264, 1319-22. PubMed
[218] Osherov, N., and Levitzki, A. (1994). Epidermal-growth-factor-dependent activation of the src-family kinases. Eur J Biochem 225, 1047-53. PubMed
[219] Posner, I., Engel, M., Gazit, A., and Levitzki, A. (1994). Kinetics of inhibition by tyrphostins of the tyrosine kinase activity of the epidermal growth factor receptor and analysis by a new computer program. Mol Pharmacol 45, 673-83. PubMed
[220] Posner, I., and Levitzki, A. (1994). Kinetics of phosphorylation of the SH2-containing domain of phospholipase C gamma 1 by the epidermal growth factor receptor. FEBS Lett 353, 155-61. PubMed
1993
[198] Anafi, M., Gazit, A., Gilon, C., Neriah, Y. B., and Levitzki, A. (1993). Tyrphostin-induced differentiation of mouse erythroleukemia cells. FEBS Lett 330, 260-4. PDF
[199] Anafi, M., Gazit, A., Zehavi, A., Ben-Neriah, Y., and Levitzki, A. (1993). Tyrphostin-induced inhibition of p210bcr-abl tyrosine kinase activity induces K562 to differentiate. Blood 82, 3524-9. PubMed
[200] Gazit, A., Osherov, N., Posner, I., Bar-Sinai, A., Gilon, C., and Levitzki, A. (1993). Tyrphostins. 3. Structure-activity relationship studies of alpha- substituted benzylidenemalononitrile 5-S-aryltyrphostins. J Med Chem 36, 3556-64. PubMed
[201] Goldberg, D., Marbach, I., Gross, E., Levitzki, A., and Simchen, G. (1993). A Candida albicans homolog of CDC25 is functional in Saccharomyces cerevisiae. Eur J Biochem 213, 195-204. PubMed
[202] Gomberg-Malool, S., Ziv, R., Re'em, Y., Posner, I., Levitzki, A., and Orly, J. (1993). Tyrphostins inhibit follicle-stimulating hormone-mediated functions in cultured rat ovarian granulosa cells. Endocrinology 132, 362-70. PubMed
[203] Levitzki, A., and Gilon, C. (1993). Tyrphostins - a novel concept for antiproliferative drugs. In Frontiers in Pharmacology and Therapeutics; Cancer Chemotherapy, J. A. Hickman and T. R. Tritton, eds.: Blackwell), pp. 107-27. N/A Online
[204] Levitzki, A., Marbach, I., and Bar-Sinai, A. (1993). The signal transduction between beta-receptors and adenylyl cyclase. Life Sci 52, 2093-100. PubMed
[205] Ohmichi, M., Pang, L., Ribon, V., Gazit, A., Levitzki, A., and Saltiel, A. R. (1993). The tyrosine kinase inhibitor tyrphostin blocks the cellular actions of nerve growth factor. Biochemistry 32, 4650-8. PubMed
[206] Osherov, N., Gazit, A., Gilon, C., and Levitzki, A. (1993). Selective inhibition of the epidermal growth factor and HER2/neu receptors by tyrphostins. J Biol Chem 268, 11134-42. PDF
[207] Perlman, R., Yablonski, D., Simchen, G., and Levitzki, A. (1993). Cloning of the STE5 gene of Saccharomyces cerevisiae as a suppressor of the mating defect of cdc25 temperature-sensitive mutants. Proc Natl Acad Sci U S A 90, 5474-8. PDF
[208] Segal, M., Willumsen, B. M., and Levitzki, A. (1993). Residues crucial for Ras interaction with GDP-GTP exchangers.Proc Natl Acad Sci U S A 90, 5564-8. PDF
[209] Smyth, M. S., Stefanova, I., Hartmann, F., Horak, I. D., Osherov, N., Levitzki, A., and Burke, T. R., Jr. (1993). Non-amine based analogues of lavendustin A as protein-tyrosine kinase inhibitors. J Med Chem 36, 3010-4. PubMed
1992
[186] Anafi, M., Gazit, A., Gilon, C., Ben-Neriah, Y., and Levitzki, A. (1992). Selective interactions of transforming and normal abl proteins with ATP, tyrosine-copolymer substrates, and tyrphostins. J Biol Chem 267, 4518-23. PDF
[187] Bar-Sinai, A., Marbach, I., and Levitzki, A. (1992). Regulation of Hormone and transmitter sensitive adenylyl cyclase.Topics in Pharmaceutical Sciences, 557-63. N/A Online
[188] Bar-Sinai, A., Marbach, I., Shorr, R. G., and Levitzki, A. (1992). The GppNHp-activated adenylyl cyclase complex from turkey erythrocyte membranes can be isolated with its beta gamma subunits. Eur J Biochem 207, 703-8. PubMed
[189] Bryckaert, M. C., Eldor, A., Fontenay, M., Gazit, A., Osherov, N., Gilon, C., Levitzki, A., and Tobelem, G. (1992). Inhibition of platelet-derived growth factor-induced mitogenesis and tyrosine kinase activity in cultured bone marrow fibroblasts by tyrphostins. Exp Cell Res 199, 255-61. PubMed
[190] Burke, T. R., Jr. , Ford, H., Osherov, N., Levitzki, A., Stefanova, I., Horak, I. D., and Marquez, V. E. (1992). Arylamides of hydroxylated isoquinolines as protein-tyrosine kinase inhibitors. Bioorganic & Medicinal Chemistry 2, 1771-4. N/A Online
[191] Gross, E., Goldberg, D., and Levitzki, A. (1992). Phosphorylation of the S. cerevisiae Cdc25 in response to glucose results in its dissociation from Ras. Nature 360, 762-5. PDF
[192] Gross, E., Marbach, I., Engelberg, D., Segal, M., Simchen, G., and Levitzki, A. (1992). Anti-Cdc25 antibodies inhibit guanyl nucleotide-dependent adenylyl cyclase of Saccharomyces cerevisiae and cross-react with a 150- kilodalton mammalian protein. Mol Cell Biol 12, 2653-61. PubMed
[193] Levitzki, A. (1992). Tyrphostins: tyrosine kinase blockers as novel antiproliferative agents and dissectors of signal transduction. Faseb J 6, 3275-82. PubMed
[194] Posner, I., Engel, M., and Levitzki, A. (1992). Kinetic model of the epidermal growth factor (EGF) receptor tyrosine kinase and a possible mechanism of its activation by EGF. J Biol Chem 267, 20638-47. PDF
[195] Rendu, F., Eldor, A., Grelac, F., Bachelot, C., Gazit, A., Gilon, C., Levy-Toledano, S., and Levitzki, A. (1992). Inhibition of platelet activation by tyrosine kinase inhibitors. Biochem Pharmacol 44, 881-8. PubMed
[196] Segal, M., Marbach, I., Engelberg, D., Simchen, G., and Levitzki, A. (1992). Interaction between the Saccharomyces cerevisiae CDC25 gene product and mammalian ras. J Biol Chem 267, 22747-51. PDF
[197] Volberg, T., Zick, Y., Dror, R., Sabanay, I., Gilon, C., Levitzki, A., and Geiger, B. (1992). The effect of tyrosine-specific protein phosphorylation on the assembly of adherens-type junctions. Embo J 11, 1733-42. PubMed
1991
[174] Bilder, G. E., Krawiec, J. A., McVety, K., Gazit, A., Gilon, C., Lyall, R., Zilberstein, A., Levitzki, A., Perrone, M. H., and Schreiber, A. B. (1991). Tyrphostins inhibit PDGF-induced DNA synthesis and associated early events in smooth muscle cells. Am J Physiol 260, C721-30. PubMed
[175] Daya-Makin, M., Pelech, S. L., Levitzki, A., and Hudson, A. T. (1991). Erbstatin and tyrphostins block protein-serine kinase activation and meiotic maturation of sea star oocytes. Biochim Biophys Acta 1093, 87-94. PubMed
[176] Dvir, A., Milner, Y., Chomsky, O., Gilon, C., Gazit, A., and Levitzki, A. (1991). The inhibition of EGF-dependent proliferation of keratinocytes by tyrphostin tyrosine kinase blockers. J Cell Biol 113, 857-65. PubMed
[177] Gazit, A., Osherov, N., Posner, I., Yaish, P., Poradosu, E., Gilon, C., and Levitzki, A. (1991). Tyrphostins. 2. Heterocyclic and alpha-substituted benzylidenemalononitrile tyrphostins as potent inhibitors of EGF receptor and ErbB2/neu tyrosine kinases. J Med Chem 34, 1896-907. PubMed
[178] Hsu, C. Y., Persons, P. E., Spada, A. P., Bednar, R. A., Levitzki, A., and Zilberstein, A. (1991). Kinetic analysis of the inhibition of the epidermal growth factor receptor tyrosine kinase by Lavendustin-A and its analogue. J Biol Chem 266, 21105-12. PDF
[179] Levitzki, A. (1991). Cellular Signaling. In Enc. of Human Biology, pp. 321-31. N/A Online
[180] Levitzki, A., and Bar-Sinai, A. (1991). The regulation of adenylyl cyclase by receptor-operated G proteins. Pharmacol Ther 50, 271-83. PubMed
[181] Levitzki, A., Gazit, A., Osherov, N., Posner, I., and Gilon, C. (1991). Inhibition of protein-tyrosine kinases by tyrphostins. Methods Enzymol 201, 347-61. PubMed
[182] Levitzki, A., and Gilon, C. (1991). Tyrphostins as molecular tools and potential antiproliferative drugs. Trends Pharmacol Sci 12, 171-4. PubMed
[183] Padeh, S., Levitzki, A., Gazit, A., Mills, G. B., and Roifman, C. M. (1991). Activation of phospholipase C in human B cells is dependent on tyrosine phosphorylation. J Clin Invest 87, 1114-8. PubMed
[184] Roifman, C. M., Chin, K., Gazit, A., Mills, G. B., Gilon, C., and Levitzki, A. (1991). Tyrosine phosphorylation is an essential event in the stimulation of B lymphocytes by Staphylococcus aureus Cowan I. J Immunol 146, 2965-71. PubMed
[185] Yoneda, T., Lyall, R. M., Alsina, M. M., Persons, P. E., Spada, A. P., Levitzki, A., Zilberstein, A., and Mundy, G. R. (1991).The antiproliferative effects of tyrosine kinase inhibitors tyrphostins on a human squamous cell carcinoma in vitro and in nude mice. Cancer Res 51, 4430-5. PubMed
1990
[166] Almagor, H., and Levitzki, A. (1990). Analytical determination of receptor-ligand dissociation constants of two populations of receptors from displacement curves. Proc Natl Acad Sci U S A 87, 6482-6. PDF
[167] Engelberg, D., Poradosu, E., Simchen, G., and Levitzki, A. (1990). Adenylyl cyclase activity of the fission yeast Schizosaccharomyces pombe is not regulated by guanyl nucleotides. FEBS Lett 261, 413-8. PubMed
[168] Engelberg, D., Simchen, G., and Levitzki, A. (1990). In vitro reconstitution of cdc25 regulated S. cerevisiae adenylyl cyclase and its kinetic properties. Embo J 9, 641-51. PubMed
[169] Levitzki, A. (1990). GTP-GDP exchange proteins. Science 248, 794. PubMed
[170] Levitzki, A. (1990). Dual control of adenylate cyclase. In G proteins as mediators of the cellular signalling process, M. D. Houslay and G. Milligan, eds.: John Wiley and Sons), pp. 1-14. PDF
[171] Levitzki, A. (1990). Tyrphostins--potential antiproliferative agents and novel molecular tools. Biochem Pharmacol 40, 913-8. PubMed
[172] Marbach, I., Bar-Sinai, A., Minich, M., and Levitzki, A. (1990). Beta subunit copurifies with GppNHp-activated adenylyl cyclase. J Biol Chem 265, 9999-10004. PDF
[173] Rendu, F., Eldor, A., Grelac, F., Levy-Toledano, S., and Levitzki, A. (1990). Tyrosine kinase blockers: new platelet activation inhibitors. Blood Coagul Fibrinolysis 1, 713-6. PubMed
1989
[158] Engelberg, D., Perlman, R., and Levitzki, A. (1989). Transmembrane signalling in Saccharomyces cerevisiae. Cell Signal 1, 1-7. PubMed
[159] Gazit, A., Yaish, P., Gilon, C., and Levitzki, A. (1989). Tyrphostins I: synthesis and biological activity of protein tyrosine kinase inhibitors. J Med Chem 32, 2344-52. PubMed
[160] Henis, Y. I., and Levitzki, A. (1989). Mammalian glyceraldehyde-3-phosphate dehydrogenase and its use toelucidate molecular mechanisms of cooperativity. In Allosteric Enzymes, G. Herve, ed.: CRC Press, Inc.), pp. 153-88. N/A Online
[161] Lyall, R. M., Zilberstein, A., Gazit, A., Gilon, C., Levitzki, A., and Schlessinger, J. (1989). Tyrphostins inhibit epidermal growth factor (EGF)-receptor tyrosine kinase activity in living cells and EGF-stimulated cell proliferation. J Biol Chem 264, 14503-9. PDF
[162] Margolis, B., Rhee, S. G., Felder, S., Mervic, M., Lyall, R., Levitzki, A., Ullrich, A., Zilberstein, A., and Schlessinger, J. (1989). EGF induces tyrosine phosphorylation of phospholipase C-II: a potential mechanism for EGF receptor signaling. Cell 57, 1101-7. PubMed
[163] Perlman, R., Eilam, Y., Padan, E., Simchen, G., and Levitzki, A. (1989). Rapid intracellular alkalinization of Saccharomyces cerevisiae MATa cells in response to alpha-factor requires the CDC25 gene product. Cell Signal 1, 577-86. PubMed
[164] Posner, I., Gazit, A., Gilon, C., and Levitzki, A. (1989). Tyrphostins inhibit the epidermal growth factor receptor-mediated breakdown of phosphoinositides. FEBS Lett 257, 287-91. PubMed
[165] Shechter, Y., Yaish, P., Chorev, M., Gilon, C., Braun, S., and Levitzki, A. (1989). Inhibition of insulin-dependent lipogenesis and anti-lipolysis by protein tyrosine kinase inhibitors. Embo J 8, 1671-6. PubMed
1988
[151] Becker, J. M., Enari, E., and Levitzki, A. (1988). Guanine nucleotide regulation of adenylate cyclase in permeabilized cells of Saccharomyces cerevisiae. Biochim Biophys Acta 968, 408-17. PubMed
[152] Levitzki, A. (1988). Signal transduction in hormone-dependent adenylate cyclase. Cell Biophys 12, 133-43. PubMed
[153] Levitzki, A. (1988). Transmembrane signalling to adenylate cyclase in mammalian cells and in Saccharomyces cerevisiae. Trends Biochem Sci 13, 298-301. PubMed
[154] Levitzki, A. (1988). From epinephrine to cyclic AMP. Science 241, 800-6. PubMed
[155] Marbach, I., and Levitzki, A. (1988). Use of electrofocusing for the analysis and purification of turkey erythrocytes beta 1-adrenoceptors. FEBS Lett 233, 186-90. PubMed
[156] Marbach, I., Shiloach, J., and Levitzki, A. (1988). Gi affects the agonist-binding properties of beta-adrenoceptors in the presence of Gs. Eur J Biochem 172, 239-46. PubMed
[157] Yaish, P., Gazit, A., Gilon, C., and Levitzki, A. (1988). Blocking of EGF-dependent cell proliferation by EGF receptor kinase inhibitors. Science 242, 933-5. PubMed
1987
[142] Daniel, J., Becker, J. M., Enari, E., and Levitzki, A. (1987). The activation of adenylate cyclase by guanyl nucleotides in Saccharomyces cerevisiae is controlled by the CDC25 start gene product. Mol Cell Biol 7, 3857-61. PubMed
[143] Horovitz, A., and Levitzki, A. (1987). An accurate method for determination of receptor-ligand and enzyme- inhibitor dissociation constants from displacement curves. Proc Natl Acad Sci U S A 84, 6654-8. PubMed
[144] Kashles, O., and Levitzki, A. (1987). Characterization of the beta 2-adrenoceptor-dependent adenylate cyclase of A431 epidermoid carcinoma cells. Biochem Pharmacol 36, 1531-8. PubMed
[145] Levitzki, A. (1987). Signal tranduction in hormone dependent adenylate cyclase. Cell Biophysics 12, 133-43. N/A Online
[146] Levitzki, A. (1987). Coupling of beta-adrenoceptors to adenylate cyclase and the role of the GTP binding protein in signal transduction. In Perspectives on Receptor Classification, J. W. Black, D. M. Jenkinson and Y. P. Gerskowitch, eds.: Alan Liss), pp. 87-94. N/A Online
[147] Levitzki, A. (1987). Regulation of adenylate cyclase by hormones and G-proteins. FEBS Lett 211, 113-8. PubMed
[148] Levitzki, A. (1987). Regulation of hormone sensitive adenylate cyclase. Trends in Pharmacol. Sci. 8, 299-303. N/A Online
[149] Levitzki, A. (1987). Cross-talk between PKC and cyclic AMP pathways. Nature 330, 319-20. PubMed
[150] Levitzki, A. (1987). Signal transduction in beta-adrenoceptor-dependent adenylate cyclase. In Enzyme Dynamics and Regulation, P. Boon Chock, C. L. Tsou, C. Y. Huang and J. H. Wang, eds.: Springer-Verlag), pp. 113-20. N/A Online
1986
[134] Bar-Sinai, A., Aldouby, Y., Chorev, M., and Levitzki, A. (1986). Association of turkey erythrocyte beta-adrenoceptors with a specific lipid component. Embo J 5, 1175-80. PubMed
[135] Feder, D., Im, M. J., Klein, H. W., Hekman, M., Holzhofer, A., Dees, C., Levitzki, A., Helmreich, E. J., and Pfeuffer, T. (1986). Reconstitution of beta 1-adrenoceptor-dependent adenylate cyclase from purified components. Embo J 5, 1509-14. PubMed
[136] Feder, D., Im, M. J., Pfeuffer, T., Hekman, M., Helmreich, E. J., and Levitzki, A. (1986). The hormonal regulation of adenylate cyclase. Biochem Soc Symp 52, 145-51. PubMed
[137] Levitzki, A. (1986). Bacterial adaptation, visual adaptation, receptor desensitization - A common link? Trends Pharmacol. Sci. 77, 3-6. N/A Online
[138] Levitzki, A. (1986). Beta-adrenergic receptors and their mode of coupling to adenylate cyclase. Physiol Rev 66, 819-54. PubMed
[139] Levitzki, A. (1986). The regulation of hormone-dependent adenylate cyclase in native membranes and systems reconstituted from purified components. In Biomembrane and Receptor Mechanisms, D. Chapman and E. Bertoli, eds. (Padua, Italy: Liviana Press), pp. 225-35. N/A Online
[140] Levitzki, A., Rudick, J., Pastan, I., Vass, W. C., and Lowy, D. R. (1986). Adenylate cyclase activity of NIH 3T3 cells morphologically transformed by ras genes. FEBS Lett 197, 134-8. PubMed
[141] Wang, L., Chorev, M., Feingers, J., Levitzki, A., and Inbar, M. (1986). Stereospecific antibodies to propranolol. FEBS Lett 199, 173-8. PubMed
1985
[131] Chorev, M., Feigenbaum, A., Keenan, A. K., Gilon, C., and Levitzki, A. (1985). N-Bromoacetyl-amino-cyanopindolol: a highly potent beta-adrenergic affinity label blocks irreversibly a non-protein component tightly associated with the receptor. Eur J Biochem 146, 9-14. PubMed
[132] Levitzki, A. (1985). Reconstitution of membrane receptor systems. Biochim Biophys Acta 822, 127-53. PubMed
[133] Levitzki, A. (1985). Receptors. In Endocytosis, I. Pastan, ed.: Plenum Press, pp. 45-68. N/A Online
1984
[121] Arad, H., Rosenbusch, J. P., and Levitzki, A. (1984). Stimulatory GTP regulatory unit Ns and the catalytic unit of adenylate cyclase are tightly associated: mechanistic consequences. Proc Natl Acad Sci U S A 81, 6579-83. PubMed
[122] Feder, D., Arad, H., Gal, A., Hekman, M., Helmreich, E. J., and Levitzki, A. (1984). Resolution, reconstitution, and mode of action of the beta-adrenergic receptor-dependent adenylate cyclase. Adv Cyclic Nucleotide Protein Phosphorylation Res 17, 61-71. PubMed
[123] Feder, D., Gal, A., and Levitzki, A. (1984). Hormone dependent adenylate cyclase: Properties and reconstitution. In Highlights in Receptor Chemisty, C. Melchiorre and M. Giannella, eds.: Elsevier Science Publishers B.V.), pp. 89-95. N/A Online
[124] Gal, A., Hekman, M., Feder, D., Helmreich, E. J. M., Pfeuffer, T., and Levitzki, A. (1984). The functional reconstitution of the beta-adrenergic receptor with the components of adenylate cyclase. In Adrenergic Receptors: Molecular Properties and Therapeutic Implications, R. J. Lefkowitz and E. Lindenlaub, eds. (Stuttgart, New York: F.K. Schattauer Verlag), pp. 369-77. PubMed
[125] Hekman, M., Feder, D., Keenan, A. K., Gal, A., Klein, H. W., Pfeuffer, T., Levitzki, A., and Helmreich, E. J. (1984).Reconstitution of beta-adrenergic receptor with components of adenylate cyclase. Embo J 3, 3339-45. PubMed
[126] Keshles, O., and Levitzki, A. (1984). The ontogenesis of beta-adrenergic receptors and of adenylate cyclase in the developing rat brain. Biochem Pharmacol 33, 3231-3. PubMed
[127] Levitzki, A. (1984). Receptor to effector coupling in the receptor-dependent adenylate cyclase system. J Recept Res 4, 399-409. PubMed
[128] Levitzki, A. (1984). b-adrenergic receptors. In Molecular Biology Approach to the Neurosciences, H. Soreq, ed.: John Wiley and Sons Ltd., pp. 73-5. N/A Online
[129] Levitzki, A. (1984). Receptors: A Quantitative Approach (Menlo Park, California: Benjamin/Cummings Publishing Company, Inc). N/A Online
[130] Levitzki, A. (1984). Where do we stand on receptors today? In Investigation of Membrane-Located Receptors, E. Reid, G. M. W. Cook and D. J. Moore, eds.: Plenum Publishing Corp., pp. 3-6. N/A Online
1983
[119] Gal, A., Braun, S., Feder, D., and Levitzki, A. (1983). Reconstitution of a functional beta-adrenergic receptor using cholate and a novel method for its functional assay. Eur J Biochem 134, 391-6. PubMed
[120] Newman, M. E., and Levitzki, A. (1983). Desensitization of normal rat kidney cells to adenosine. Biochem Pharmacol 32, 137-40. PubMed
1982
[109] Braun, S., Arad, H., and Levitzki, A. (1982). The interaction of Mn2+ with turkey erythrocyte adenylate cyclase.Biochim Biophys Acta 705, 55-62. PubMed
[110] Braun, S., Tolkovsky, A. M., and Levitzki, A. (1982). Mechanism of control of the turkey erythrocyte beta-adrenoceptor dependent adenylate cyclase by guanyl nucleotides: a minimum model. J Cyclic Nucleotide Res 8, 133-47. PubMed
[111] Braun, S., Tolkovsky, A. M., Steer, M. L., Lester, H. A., and Levitzki, A. (1982). Activation and inhibition of adenylate cyclase by hormones. Biochem Soc Trans 10, 496-8. PubMed
[112] Keenan, A. K., Gal, A., and Levitzki, A. (1982). Reconstitution of the turkey erythrocyte adenylate cyclase sensitivity to 1-epinephrine upon re-insertion of the Lubrol solubilized components into phospholipid vesicles. Biochem Biophys Res Commun 105, 615-23. PubMed
[113] Lester, H. A., Steer, M. L., and Levitzki, A. (1982). Prostaglandin-stimulated GTP hydrolysis associated with activation of adenylate cyclase in human platelet membranes. Proc Natl Acad Sci U S A 79, 719-23. PubMed
[114] Levitzki, A. (1982). The mode of coupling of beta-adrenergic receptors to adenylate cyclase. In Topics in Molecular Pharmacology, A. S. V. Burgen and G. C. K. Roberts, eds. (Amsterdam, North Holland: Elsevier), pp. 23-62. N/A Online
[115] Newman, M., and Levitzki, A. (1982). Characteristics of high-affinity [3H]adenosine binding to rat brain synaptosomes and turkey erythrocyte membranes. Biochim Biophys Acta 685, 129-36. PubMed
[116] Steer, M. L., Braun, S., Lester, H. A., and Levitzki, A. (1982). Activation and inhibition of human platelet adenylate cyclase byhormones and guanyl nucleotides. J. Cycl. Nucl. Res 8, 309-22. N/A Online
[117] Steer, M. L., Braun, S., Lester, H. A., and Levitzki, A. (1982). Activation of adenylate cyclase from purified platelet membranes by prostaglandin E1 and its inhibition by L-epinephrine: mechanistic effects. J Cyclic Nucleotide Res 8, 309-22. PubMed
[118] Tolkovsky, A. M., Braun, S., and Levitzki, A. (1982). Kinetics of interaction between beta-receptors, GTP protein, and the catalytic unit of turkey erythrocyte adenylate cyclase. Proc Natl Acad Sci U S A 79, 213-7. PubMed
1981
[101] Arad, H., Rimon, G., and Levitzki, A. (1981). The reversal of the Gpp(NH)p-activated state of adenylate cyclase by GTP and hormone is by the "collision coupling" mechanism. J Biol Chem 256, 1593-7. PDF
[102] Henis, Y. I., and Levitzki, A. (1981). The mechanism of negative cooperativity in rabbit muscle glyceraldehyde- 3-phosphate dehydrogenase. Ann N Y Acad Sci 366, 217-36. PubMed
[103] Levitzki, A. (1981). Negative cooperativity in the insulin receptor: Alexander Levitzki examines the evidence. Nature 289, 442-3. N/A Online
[104] Levitzki, A. (1981). The beta-adrenergic receptor and its mode of coupling to adenylate cyclase. CRC Crit Rev Biochem 10, 81-112. PubMed
[105] Levitzki, A., and Atlas, D. (1981). A possible molecular mechanism for beta-receptor desensitization: experiments and hypotheses. Life Sci 28, 661-72. PubMed
[106] Porath-Furedi, A., and Levitzki, A. (1981). Outward pressure within erythrocytes. Isr J Med Sci 17, 36-40. PubMed
[107] Tamir, A., Rigbi, M., and Levitzki, A. (1981). The interaction of chlorpromazine and butyrophenones with glutamate dehydrogenase. Biochem Pharmacol 30, 1469-73. PubMed
[108] Tolkovsky, A. M., and Levitzki, A. (1981). Theories and predictions of models describing sequential interactions between the receptor, the GTP regulatory unit, and the catalytic unit of hormone dependent adenylate cyclases. J Cyclic Nucleotide Res 7, 139-50. PubMed
1980
[87] Atlas, D., Volsky, D. J., and Levitzki, A. (1980). Lateral mobility of beta-receptors involved in adenylate cyclase activation. Biochim Biophys Acta 597, 64-9. PubMed
[88] Davies, P. J., Davies, D. R., Levitzki, A., Maxfield, F. R., Milhaud, P., Willingham, M. C., and Pastan, I. H. (1980).Transglutaminase is essential in receptor-mediated endocytosis of alpha 2-macroglobulin and polypeptide hormones.Nature 283, 162-7. PubMed
[89] Henis, Y. I., and Levitzki, A. (1980). Mechanism of negative cooperativity in glyceraldehyde-3-phosphate dehydrogenase deduced from ligand competition experiments. Proc Natl Acad Sci U S A 77, 5055-59. PubMed
[90] Henis, Y. I., and Levitzki, A. (1980). The sequential nature of the negative cooperativity in rabbit muscle glyceraldehyde-3-phosphate dehydrogenase. Eur J Biochem 112, 59-73. PubMed
[91] Hill, T. L., and Levitzki, A. (1980). Subunit neighbor interactions in enzyme kinetics: half-of-the-sites reactivity in a dimer. Proc Natl Acad Sci U S A 77, 5741-5. PubMed
[92] Levitzki, A. (1980). GTP-receptor interrelationships in adenylate cyclase systems. Theoretical considerations.Biochim Biophys Acta 628, 419-24. PubMed
[93] Levitzki, A. (1980). Catecholamine receptors. In Receptors from Hormones and Neurotransmitters, D. Schulster and A. Levitzki, eds. (London: John Wiley & Sons), pp. 267-86. N/A Online
[94] Levitzki, A. (1980). Quantitative aspects of ligand binding to receptors. In Cellular Receptors for Hormones and Neurotransmitters, D. Schulster and A. Levitzki, eds. (London: John Wiley & Sons), pp. 9-28. N/A Online
[95] Levitzki, A. (1980). Slow GDP dissociation from the guanyl nucleotide site of turkey erythrocyte membranes is not the rate limiting step in the activation of adenylate cylase by beta-adrenergic receptors. FEBS Lett 115, 9-10. PubMed
[96] Levitzki, A. (1980). The coupling of receptors to adenylate cyclases [proceedings]. Psychopharmacol Bull 16, 17-9. PubMed
[97] Levitzki, A., Willingham, M., and Pastan, I. (1980). Evidence for participation of transglutaminase in receptor-mediated endocytosis. Proc Natl Acad Sci U S A 77, 2706-10. PubMed
[98] Rimon, G., Hanski, E., and Levitzki, A. (1980). Temperature dependence of beta receptor, adenosine receptor, and sodium fluoride stimulated adenylate cyclase from turkey erythrocytes. Biochemistry 19, 4451-60. PubMed
[99] Schulster, D., and Levitzki, A. (1980). Receptors for Hormones and Neurotransmitters , D. Schulster and A. Levitzki, eds.: John Wiley & Sons). N/A Online
[100] Tolkovsky, A. M., and Levitzki, A. (1980). Molecular models for receptor to adenylate cyclase coupling. In Mathematical Models in Molecular and Cellular Biology, L. A. Segel, ed. (Cambridge: Cambridge University Press), pp. 111-21. N/A Online
1979
[79] Arad, H., and Levitzki, A. (1979). The mechanism of partial agonism in the beta-receptor dependent adenylate cyclase of turkey erythrocytes. Mol Pharmacol 16, 749-56. PubMed
[80] Atlas, D., Hanski, E., and Levitzki, A. (1979). Re-evaluation of the number of specific beta-adrenergic receptors on muscle cells. Nature 277, 58-60. N/A Online
[81] Braun, S., and Levitzki, A. (1979). Adenosine receptor permanently coupled to turkey erythrocyte adenylate cyclase.Biochemistry 18, 2134-8. PubMed
[82] Braun, S., and Levitzki, A. (1979). The attenuation of epinephrine-dependent adenylate cyclase by adenosine and the characteristics of the adenosine stimulatory and inhibitory sites. Mol Pharmacol 16, 737-48. PubMed
[83] Hanski, E., Rimon, G., and Levitzki, A. (1979). Adenylate cyclase activation by the beta-adrenergic receptors as a diffusion-controlled process. Biochemistry 18, 846-53. PubMed
[84] Henis, Y. I., and Levitzki, A. (1979). Ligand competition curves as a diagnostic tool for delineating the nature of site-site interactions: theory. Eur J Biochem 102, 449-65. PubMed
[85] Henis, Y. I., Levitzki, A., and Gafni, A. (1979). Evidence for ligand-induced conformational changes in rabbit-muscle glyceraldehyde-3-phosphate dehydrogenase. Eur J Biochem 97, 519-28. PubMed
[86] Levitzki, A., and Helmreich, E. J. (1979). Hormone-receptor--adenylate cyclase interactions. FEBS Lett 101, 213-9. PubMed
1978
[68] Atlas, D., and Levitzki, A. (1978) Tentative identification of beta-adrenoreceptor subunts. Nature 272, 370-1. PubMed
[69] Atlas, D., and Levitzki, A. (1978). Fluorescent visualization of beta-adrenergic receptors on cell surfaces. FEBS Lett 85, 158-62. PubMed
[70] Bakadjieva, A., Galla, J. J., Helmreich, E. J. M., and Levitzki, A. (1978). The modulation of receptor-adenylate cyclase interactions by membrane fluidization. In Hormones and Cell Regulation, J. Dumont and J. Nunez, eds. (North Holland: Elsevier), pp. 11-27. N/A Online
[71] Hanski, E., and Levitzki, A. (1978). The absence of desensitization in the beta adrenergic receptors of turkey reticulocytes and erythrocytes and its possible origin. Life Sci 22, 53-60. PubMed
[72] Levitzki, A. (1978). The mode of coupling of adenylate cyclase to hormone receptors and its modulation by GTP. Biochem Pharmacol 27, 2083-8. PubMed
[73] Levitzki, A. (1978). Catecholamine receptors. Rev Physiol Biochem Pharmacol 82, 1-26. PubMed
[74] Levitzki, A. (1978). Quantitative aspects of allosteric mechanisms. Mol Biol Biochem Biophys 28, 1-106. PubMed
[75] Rimon, G., Hanski, E., Braun, S., and Levitzki, A. (1978). Mode of coupling between hormone receptors and adenylate cyclase elucidated by modulation of membrane fluidity. Nature 276, 394-6. PubMed
[76] Tolkovsky, A. M., and Levitzki, A. (1978). Collision coupling of the b-adrenergic receptor with adenylate cyclase. In Hormones and Cell Regulation, J. Dumont and J. Nunez, eds. (North-Holland: Elsevier), pp. 89-105. N/A Online
[77] Tolkovsky, A. M., and Levitzki, A. (1978). Coupling of a single adenylate cyclase to two receptors: adenosine and catecholamine.Biochemistry 17, 3811-7. PubMed
[78] Tolkovsky, A. M., and Levitzki, A. (1978). Mode of coupling between the beta-adrenergic receptor and adenylate cyclase in turkey erythrocytes. Biochemistry 17, 3795. PubMed
1977
[60] Atlas, D., Hanski, E., and Levitzki, A. (1977). Eighty thousand beta-adrenoreceptors in a single cell. Nature 268, 144-6. PubMed
[61] Atlas, D., and Levitzki, A. (1977). Probing of beta-adrenergic receptors by novel fluorescent beta- adrenergic blockers. Proc Natl Acad Sci U S A 74, 5290-4. PubMed
[62] Epstein, M., Reuben, J., and Levitzki, A. (1977). Calcium binding site of trypsin as probed by lanthanides. Biochemistry 16, 2449-57. PubMed
[63] Hanski, E., Sevilla, N., and Levitzki, A. (1977). The allosteric inhibition by calcium of soluble and partially purified adenylate cyclase from turkey erythrocytes. Eur J Biochem 76, 513-20. PubMed
[64] Henis, Y. I., and Levitzki, A. (1977). The role of the nicotinamide and adenine subsites in the negative co- operativity of coenzyme binding to glyceraldehyde-3-phosphate dehydrogenase. J Mol Biol 117, 699-716. PubMed
[65] Levitzki, A. (1977). The role of GTP in the activation of adenylate cyclase. Biochem Biophys Res Commun 74, 1154-9. PubMed
[66] Sevilla, N., and Levitzki, A. (1977). The activation of adenylate cyclase by 1-epinephrine and guanylylimidodiphosphate and its reversal by 1-epinephrine and GTP. FEBS Lett 76, 129-34. PubMed
[67] Sevilla, N., Tolkovsky, A. M., and Levitzki, A. (1977). Activation of turkey erythrocyte adenylate cyclase by two receptors: adenosine and catecholamines. FEBS Lett 81, 339-41. PubMed
1976
[48] Atlas, D., and Levitzki, A. (1976). An irreversible blocker for the beta-adrenergic receptor. Biochem Biophys Res Commun 69, 397-403. PubMed
[49] Atlas, D., Steer, M. L., and Levitzki, A. (1976). Affinity label for beta-adrenergic receptor in turkey erythrocytes. Proc Natl Acad Sci U S A 73, 1921-5. PubMed
[50] Henis, Y. I., and Levitzki, A. (1976). An analysis on the slope of Scatchard plots. Eur J Biochem 71, 529-32. PubMed
[51] Levitzki, A. (1976). Membrane receptor function. In Hormone and Antihormone Action at the Target Cell, J. M. Clark, W. Klee, A. Levitzki and J. Wolff, eds. (Berlin: Dahlem Conferenzen), pp. 79-86. N/A Online
[52] Levitzki, A. (1976). Catecholamine receptors. In Hormone and Antihormone Action at the Target Cell, J. M. Clark, W. Klee, A. Levitzki and J. Wolff, eds. (Berlin: Dahlem Conferenzen), pp. 187-202. N/A Online
[53] Levitzki, A. (1976). Characterization of the b-adrenergic receptor and the regulatory control of adenylate cyclase. In Surface Membrane Receptors, R. A. Bradshaw, W. F. Frazier, R. C. Merrell, D. I. Gottlieb and R. A. Hogue-Angeletti, eds. (New York: Plenum Press Publishing Co.), pp. 405-18. N/A Online
[54] Levitzki, A., and Koshland, D. E., Jr. (1976). The role of negative cooperativity and half-of-the-sites reactivity in enzyme regulation.Curr Top Cell Regul 10, 1-40. PubMed
[55] Levitzki, A., Sevilla, N., and Steer, M. L. (1976). The regulatory control of beta-receptor dependent adenylate cyclase. J Supramol Struct 4, 405-18. PubMed
[56] Lifshitz, R., and Levitzki, A. (1976). Identity and properties of the chloride effector binding site in hog pancreatic alpha-amylase.Biochemistry 15, 1987-93. PubMed
[57] Sevilla, N., Steer, M. L., and Levitzki, A. (1976). Synergistic activation of adenylate cyclase by guanylyl imidophosphate and epinephrine. Biochemistry 15, 3493-9. PubMed
[58] Steer, M. L., Baldwin, C., and Levitzki, A. (1976). Preparation and characterization of hormone-sensitive, resealed erythrocyte ghosts. J Biol Chem 251, 4930-5. PDF
[59] Tenenbaum-Bayer, H., and Levitzki, A. (1976). The refolding of lactate dehydrogenase subunits and their assembly to the functional tetramer. Biochim Biophys Acta 445, 261-79. PubMed
1975
[40] Levitzki, A. (1975). The quantitative aspects of drug-receptor interactions. J Mol Biol 97, 46-53. PubMed
[41] Levitzki, A. (1975). Subunit interactions in proteins. In Subunit Enzymes: Structure and Function, K. E. Ebner, ed. (New York: Marcel Decker), pp. 1-41. N/A Online
[42] Levitzki, A., Segel, L. A., and Steer, M. L. (1975). Co-operative response of oligomeric protein receptors coupled to non-co- operative ligand binding. J Mol Biol 91, 125-30. PubMed
[43] Levitzki, A., Sevilia, N., Atlas, D., and Steer, M. L. (1975). Ligand specificity and characteristics of the beta-adrenergic receptor in turkey erythrocyte plasma membranes. J Mol Biol 97, 35-46. PubMed
[44] Schlessinger, J., Steinberg, I. Z., and Levitzki, A. (1975). A comparative study of NAD+ binding sites in dehydrogenases by circular polarization of fluorescence. J Mol Biol 91, 523-8. PubMed
[45] Steer, M. L., Atlas, D., and Levitzki, A. (1975). Inter-relations between beta-adrenergic receptors, adenylate cyclase and calcium. N Engl J Med 292, 409-14. PubMed
[46] Steer, M. L., and Levitzki, A. (1975). The control of adenylate cyclase by calcium in turkey erythrocyte ghosts. J Biol Chem 250, 2080-4. PDF
[47] Steer, M. L., and Levitzki, A. (1975). The interaction of catecholamines, Ca2+ and adenylate cyclase in the intact turkey erythrocyte. Arch Biochem Biophys 167, 371-6. PubMed
1974
[29] Atlas, D., Steer, M. L., and Levitzki, A. (1974). Stereospecific binding of propranolol and catecholamines to the beta- adrenergic receptor. Proc Natl Acad Sci U S A 71, 4246-8. PubMed
[30] Epstein, M., Levitzki, A., and Reuben, J. (1974). Binding of lanthanides and of divalent metal ions to porcine trypsin. Biochemistry 13, 1777-82. PubMed
[31] Koshland, D. E., Jr., and Levitzki, A. (1974). CTP synthetase and related enzymes. In The Enzymes, P. D. Boyer, ed., pp. 539-59. N/A Online
[32] Levitzki, A. (1974). Half-of-the-sites and all-of-the-sites reactivity in rabbit muscle glyceraldehyde 3-phosphate dehydrogenase. J Mol Biol 90, 451-68. PubMed
[33] Levitzki, A. (1974). Negative co-operativity in clustered receptors as a possible basis for membrane action. J Theor Biol 44, 367-72. PubMed
[34] Levitzki, A., Atlas, D., and Steer, M. L. (1974). The binding characteristics and number of beta-adrenergic receptors on the turkey erythrocyte. Proc Natl Acad Sci U S A 71, 2773-6. PubMed
[35] Levitzki, A., and Schlessinger, J. (1974). Cooperativity in associating proteins. Monomer-dimer equilibrium coupled to ligand binding. Biochemistry 13, 5214-9. PubMed
[36] Levitzki, A., and Steer, M. L. (1974). The allosteric activation of mammalian alpha-amylase by chloride. Eur J Biochem 41, 171-80. PubMed
[37] Levitzki, A., and Tenenbaum, H. (1974). Dimers as intermediates in the assembly of tetrameric proteins: A study of lactate dehydrogenase isozymes. Israel J. Chem. 12, 327-37. N/A Online
[38] Schlessinger, J., and Levitzki, A. (1974). Molecular basis of negative co-operativity in rabbit muscle glyceraldehyde-3-phosphate dehydrogenase. J Mol Biol 82, 547-61. PubMed
[39] Steer, M. L., Tal, N., and Levitzki, A. (1974). The role of sulfhydryl groups in the action and structure of mammalian -amylase. Biochem. Biophys. Acta 334, 389-97. PubMed
1973
[26] Levitzki, A. (1973). Ligand induced half-of-the-sites reactivity in rabbit muscle glyceraldehyde-3-phosphate dehydrogenase. Biochem Biophys Res Commun 54, 889-93. PubMed
[27] Levitzki, A., and Reuben, J. (1973). Abortive complexes of -amylases with lanthanides. Biochemistry 12, 41-4. PubMed
[28] Steer, M. L., and Levitzki, A. (1973). The metal specificity of mammalian -amylase as revealed by enzyme activity and structural probes. FEBS Lett 31, 89-92. PubMed
1972
[21] Levitzki, A. (1972). The assembly pathway of lactic dehydrogenase isozymes from their unfolded subunits. FEBS Lett 24, 301-304. PDF
[22] Levitzki, A., and Koshland, D. E., Jr. (1972). Ligand-induced dimer-to-tetramer transformation in cytosine triphosphate synthetase. Biochemistry 11, 247-53. PubMed
[23] Levitzki, A., and Koshland, D. E., Jr. (1972). Role of an allosteric effector. Guanosine triphosphate activation in cytosine triphosphate synthetase. Biochemistry 11, 241-6. PubMed
[24] Levitzki, A., Pecht, I., and Berger, A. (1972). The copper-poly-L-histidine complexes. II. Physicochemical properties. J Am Chem Soc 94, 6844-8. PubMed
[25] Wachman, A., and Levitzki, A. (1972). Mechanism for the assembly of spherical viruses: a geometrical approach. J Theor Biol 34, 277-87. PubMed
1971
[18] Levitzki, A., and Berger, A. (1971). Specific oxidation of copper binding sites in copper(II)--oligopeptide complexes. Biochemistry 10, 64-6. PubMed
[19] Levitzki, A., and Koshland, D. E., Jr. (1971). Cytidine triphosphate synthetase. Covalent intermediates and mechanisms of action. Biochemistry 10, 3365-71. PubMed
[20] Levitzki, A., Stallcup, W. B., and Koshland, D. E., Jr. (1971). Half-of-the-sites reactivity and the conformational states of cytidine triphosphate synthetase. Biochemistry 10, 3371-8. PubMed
1970
[14] Kirschner, I., Citri, N., Levitzki, A., and Anbar, M. (1970). The effect of copper on the radiosensitivity of bacteria. Int J Radiat Biol Relat Stud Phys Chem Med 17, 81-5. PubMed
[15] Levitzki, A. (1970). Determination of submicro quantities of ammonia. Anal Biochem 33, 335-40. PubMed
[16] Levitzki, A., and Koshland, D. E., Jr. (1970). Ligand-induced association-dissociation as a means for enzyme purification. Biochim Biophys Acta 206, 473-5. PubMed
[17] Long, C. W., Levitzki, A., and Koshland, D. E., Jr. (1970). The subunit structure and subunit interactions of cytidine triphosphate synthetase. J Biol Chem 245, 80-7. PDF
1969
[12] Levitzki, A., and Koshland, D. E., Jr. (1969). Negative cooperativity in regulatory enzymes. Proc Natl Acad Sci U S A 62, 1121-8. PubMed
[13] Levitzki, A., and Koshland, D. E., Jr. (1969). The regulation of enzyme action by negative cooperativity. FEBS Symposium on Metabolic Regulations and Enzyme Action 19, 263-270. N/A Online
1968
[8] Kalb, A. J., and Levitzki, A. (1968). Metal-binding sites of concanavalin A and their role in the binding of alpha-methyl d-glucopyranoside. Biochem J 109, 669-72. PubMed
[9] Levitzki, A. (1968). The physicochemical properties of the poly-L-histidine Cu (II) complex. In Progress in Coordination Chemistry, M. Cais, ed.: Elsevier Publishing Co.), pp. 480-2. N/A Online
[10] Levitzki, A., and Anbar, M. (1968). Formation of Bis (biuretato)-complex of tervalent copper and its redox potential. Chem. Commun., 403. N/A Online
[11] Yariv, J., Kalb, A. J., and Levitzki, A. (1968). The interaction of concanavalin A with methyl alpha-D-glucopyranoside. Biochim Biophys Acta 165, 303-5. PubMed
1967
[5] Levitzki, A., and Anbar, M. (1967). Modification of the radiolytic oxidation of ribonuclease induced by bound copper. J Am Chem Soc 89, 4185-9. PubMed
[6] Levitzki, A., Anbar, M., and Berger, A. (1967). Specific oxidation of peptides via their copper complexes. Biochemistry 6, 3757-65. PubMed
[7] Pecht, I., Levitzki, A., and Anbar, M. (1967). The copper-poly-L-histidine complex. I. The environmental effect of the polyelectrolyte on the oxidase activity of copper ions. J Am Chem Soc 89, 1587-91. PubMed
1966

[4] Levitzki, A., and Anbar, M. (1966). Copper induced radiolytic in activation of a-amylase and catalase. Rad. Res. 27, 32-40.

N/A Online

1965
[3] Levitzki, A., Pecht, I., and Anbar, M. (1965). Oxidase-like activity of the copper-poly-L-histidine complex. Nature 207, 1386-7. N/A Online
1964
[2] Levitzki, A., and Schramm, M. (1964). Specific precipitation of enzymes by its substrate: The amylase macrodextrin complex. Biochem. Biophys. Acta 81, 101-7. N/A Online
1963

Demo Content

Patents

A. Levitzki, C. Gilon, M. Chorev and A. Gazit. Pharmaceutical Compositions comprising Benzylidene and Cinnamylidene Malononitrile Derivatives for the Inhibition of Proliferative Processes in Mammalian Cell. Certain such novel compounds and their preparation. PCT Int. Appl. WO 91 16,892, C.A. 117, 48,118f (1992).

 

USA patent 5,196,446, 23.3.1993 A. Levitzki, C. Gilon and A. Gazit. Certain indole compounds which inhibit EGF receptor tyrosine kinase.

 

USA patent 5,217, 999, 8.6.1993 A. Levitzki, C. Gilon, M. Chorev and A. Gazit. Styryl compounds which inhibit EGF receptor protein tyrosine kinase.

 

USA patent 5,302,606, 12.4.1994 A. Spada, P.E. Persons, A. Levitzki, C. Gilon and A. Gazit. Styryl substituted Pyridyl compounds which inhibit EGF receptor tyrosine kinase.

 

USA patent 5,656,655 , A. Spada, P.E. Persons, A. Levitzki, C. Gilon and A. Gazit. Styryl substituted heteroaryl compounds which inhibit EGF receptor tyrosine kinase.

 

USA patent 5,712,395,27.1.1998. H. App, G.M. McMahon, P.C. Tang, A. Gazit and A. Levitzki. Compounds for the treatments of disorders related to vasculogenesis and/or angiogenesis.

 

USA patent 5,763,441, 6.1.1998. H.App,G.M.McMahon,P.C.Tang,A.Gazit and A.Levitzki. Compounds for the treatments of disorders related to vasculogenesis and/or angiogenesis.

 

USA patent 5,773,476,30.6.1998. H.Chen,A.Gazit, A.Levitzki, K.P.Hirth, E.Mann, L.K.Shawyer, J.Tsai and P.C.Tang. Methods and compositions for inhibiting cell proliferative disorders

 

<p ">USA patent 5,789,427 ,4.8.1998. H.Chen,A.Gazit,K.P.Hirth,E.Mann,J.Tsai and P.C,Tang. Methods and compositions for inhibiting cell proliferative disorders.

 

USA patent 5,792,771 ,11.8.1998. H.App, G.M.McMahon,P.C.Tang,A.Gazit and A.Levitzki. Quinazoline compounds and compositions thereof for the treatment of disease.

 

USA patent 5,849,742 ,15.12.1998 . G.M.McMahon,P.C.Tang,A.Gazit and A.Levitzki. Compounds for the treatments of disorders related to vasculogenesis and/or angiogenesis.

 

US patent 5,932,580, Aug. 3, 1999. A. Levitzki, A. Gazit, S. Banai, G. Golomb, D. Gertz. PDGF Receptor Kinase Inhibitory Compounds and their Preparation and Compositions.

 

US patent 6,126,917, Oct 3,2000. E.Mishani, T.Bonasera,G. Ortu, Y.Rozen, A.Gazit and A.Levitzki. Epidermal Growth Factor Receptor Binding Compounds for Positron Emission Tomography.

 

US Patent 6,358,954, March 19, 2002. A. Levitzki, A. Gazit, S. Banai, G. Golomb, D. Gertz. PDGF Receptor Kinase Inhibitory Compounds. Their Preparation, Purification and pharmaceutical compositions including same.

 

U.S. Patent US60/872,511 (2006). Alexander Levitzki,Dr.Hadas Reuveni. Substrate competitive tyrosine kinase inhibitors.

 

U.S. Patent 7,172,749(2007). E. Mishani, Y. Rozen, G. Abourbeh, A. Levitzki. Novel EGFR-TK irreversible inhibitors for cancer therapy, radiotherapy and diagnosis.

 

Patent Applications

 

A. Levitzki, A. Gazit, C. Gilon and Y. Ben-Neriah, Israeli patent No. 105707, 14.5.1993. Tyrphostins and compositions containing them.

 

Abl- USA patent applications, 08-234,327 and 08-236.420, 28.4.94. Methods and compounds for inhibiting cell proliferative disorders characterized by abnormal abl activity.

 

US patent application 08-231,717, 30.9.94. C. Roifman, A. Gazit and A. Levitzki, Composition and methods for treating Leukemia.

 

A. Levitzki, A. Gazit and A. Novogrodsky. Israeli patent appl. 107.736, Tyrphostins for preventing septic shock ,1996

 

H-J. Su Huang, M. Nagane, W.K. Cavenee, A. Levitzki, A. Gazit. Methods to Modulate the Resistance of Cells to Apoptosis Mediated by Mutant Epidermal Growth Factor Receptors. U.S.patent applications 09-071,541, 11.8.98.

 

Alexei Shir and Alexander Levitzki. Selective killing of cells by activation of double stranded RNA dependent protein kinase PKRUS patent application, submitted January 2, 2001

 

A. Gazit and A. Levitzki. 4-Anilido Substituted quinazolines and use thereof as inhibitors of epidermal growth factor receptor .Reference number: P-4579-USP (175510).Submitted August 1, 2002

 

A. Levitzki. Kinase Compounds, Field of Invention. Reference number: P-5265-USP

 

E. Mishani, I. Ben-David, Y. Rozen, G. Ortu, A. Levitzki. Radiolabeled irreversible inhibitors of epidermal growth factor receptor tyrosine kinase and their use in radioimaging and radiotherapy. U.S. Patent Application No. 09/802,928. Reference Number: 2572-00. Filed: Mar. 12, 2001

 

A. Shir and A. Levitzki. Efficient Killing of Giloblastoma and Other Cancers by Cancer Specific Transfection of dsRNA.Reference number: 60/426,876. Submitted: November 18, 2002

 

A. Levitzki. Novel EGFR-TK Irreversible Inhibitors for Cancer Therapy, Radiotherapy and Diagnosis .Reference number: 2759-00. Submitted: January 23, 2003

 

A. Levitizki and E. Mishani. Provisional Novel EGFR-TK Irreversible Inhibitors for Cancer Therapy Radiotherapy and Diagnosis .Reference number: 2741-00. Submitted: Feb. 13, 2003

A. Levitzki and E. Mishani. Provisional Novel EGFR-TK Irreversible Inhibitors for Cancer Therapy Radiotherapy and Diagnosis .Reference number: 2741-00.Submitted: Feb. 13, 2003

 

A. Levitzki, A. Gazit, G. Blum Cathecol Bio-Isosteres Reference number: 2633.01. Filed: Feb. 05, 2003

 

A. Levitzki, A. Gazit Non-myeloablative tolerogenic treatment with tyrphostins Reference number: 2590.01. PCT Application No. PCT/IL02/00467. Filed: June 16,2002

 

A. Levitzki PDGF Receptor Kinase Inhibitory compounds and compositions, methods for synthesis of same and use of same for treatment of proliferative disorders. Reference number: 2367.04. Australian Patent Application No. 16108/99

 

W. Priebe, N. Donato, M. Talpaz Szymanski Slawomir, Fokt Izabela, Levitzki Alexander . Novel Compounds for Treatment of Cell Proliferative Diseases Ref No. UTSC: 832USP1 .MDA03-123

 

A. Levitzki, A.Gazit, S. Banai, S.David Gertz, G.Golomb, G.D. Boehmer and J. Waltenberger . PDGF Receptor Kinase Inhibitory compounds and compositions, their preparation, purification and pharmaceutical compositions including same Reference number: 2466.08 U.S. Patent Application No. 09/828,602

 

A. Shir, A. Levitzki. Targeted Double Stranded RNA mediated cell killing Ref. No: 2729-01 U.S. Patent Application No. 60/426,876

 

H.J. Huang, A. Gazit. A. Levitzki. Methods to modulate the resistance of cells to apoptosis mediated by mutant epidermal growth factor receptors Ref. No.: LUD 5553.US Patent Application No.040750-5001-01

 

Levitzki A, Gazit A. Non-Myeloablative tolerogenic treatment with tyrphostins. Number : WO 03/065971

 

W.Priebe, N.Donato, M.Talpaz Szymanski Slawomir,Fokt Izabela, Levitzki Alexander. Novel Compounds for Treatment of Cell Proliferative Diseases.Ref No.UTSC:832USP1, MDA03-123

 

N.Livnah,A.LevitzkiH.Senderovitz,T.Yechezkel,,Y.Saltira,P.Litman and O.Ohne. Cell permeable conjugates of peptides for inhibition of protein kinases. IPN WO 2004/110337 A2 (PCT)

Current Research Activities

Signal Transduction Therapy

(References refer to the list of publications)
Alexander Levitzki has made numerous contributions to the field of enzyme regulation and signal transduction for the past 50 years. These achievements culminated in the paradigm shift in the treatment of cancers and leukemias. In the 1980s the Levitzki laboratory pioneered signal transduction therapy, (a term he actually coined). The Levitzki laboratory was the first to develop systematically tyrosine phosphorylation inhibitors, also known as tyrosine kinase inhibitors, (Tyrphostins/TKIs) that selectively block tyrosine kinases and not Ser/Thr kinases. Initially, Levitzki’s claim met with skepticism from the key experts on protein kinases, who argued that the degree of conservation between protein kinase domains precludes the possibility of generating low molecular weight selective inhibitors that discriminate between serine/threonine kinases and tyrosine kinases, let alone between tyrosine kinases. In 1988, in a seminal paper158 Levitzki reported on Tyrphostins/tyrosine kinase inhibitors that do not inhibit Ser/Thr kinases and at the same time selectively inhibit EGFR as compared to the insulin receptor. These two proteins were the only tyrosine kinases available at that time in a pure and active form. Between 1988 and 1996 Levitzki and his group developed specific tyrosine kinase inhibitors (tyrphostins) targeting:
(1)EGFR (158,160,219)
(2)Her-2 (178,201,207), here the Levitzki laboratory demonstrated that although the kinase domains of Her2 and EGFR are highly homologous they could synthesize selective Her2 kinase inhibitors!
(3) PDGFR (214,230,231,241), here the Levitzki laboratory showed that ATP competitive inhibitors can discriminate between PDGFR and EGFR
(4) VEGFR2 (236) (anti-angiogenic agents)
(5) Bcr-Abl (187,199,213)
(6) Jak2 (235) and later
(7) IGF1R (247,269,306,353,382).
The inhibitors Levitzki developed are: substrate-competitive, ATP-competitive, bi-ATP/substrate-competitive inhibitors as well as “mixed” competitive inhibitors from diverse chemical scaffolds 221,225,338 (and all of the above).  
The inhibitors developed by the Levitzki laboratory cover a large variety of chemical scaffolds for generating the wide spectrum of tyrosine phosphorylation inhibitors, which guided the pharmaceutical industry ever since 1988. Due to the prevailing skepticism concerning the ability to generate selective tyrosine kinase inhibitors and the fact that Levitzki was a “newcomer” to the field, his laboratory was practically left alone until 1996 in a field, he actually created! That year, the first Gleevec paper came out, acknowledging Levitzki’s 1988-1993 pioneering work, stating that they were following Levitzki’s pioneering work on Bcr-Abl and EGFR. This was quickly followed by Tarceva , Iressa and Suntinib (the latter was co-developed by Levitzki with Sugen in the 1990s236, now marketed by Pfizer).
Levitzki’s work refocused the pharmaceutical industry, spearheaded by Novartis whose CEO acknowledges (enclosed) the key role of Levitzki, in his book “The Cancer Magic Bullet” (2003), later echoed by the President of US ASBMB (2007) citing that the breakthrough came from Academia. Asof 2017 there are 26 Tyrphostins/TKIs in the clinic (381) and dozens are in development. About 30% of the effort of the pharmaceutical industry is in the tyrosine  kinase inhibitor field, which Levitzki pioneered.
In 1995 Levitzki was invited by Science to write a review on tyrosine kinase inhibition as a therapeutic modality, a year before the first Gleevec paper appeared!, and just when the field started to take off. Levitzki also pioneered the idea to combine kinase inhibitors with chemotherapy(194,215,237) and antibodies186 in “smart cocktails”194.

Inhibiting the tumor microenvironment

In 2016 the Levitzki laboratory discovered an inhibitor that targets both IGF1R382 signaling and Stat3 signaling390, thus inhibiting both the tumor and its conducive tumor microenvironment391. This inhibitor and its family members represent a first-in-class class of inhibitors that target two independent oncogenic pathways and at the same time inhibits the pro-oncogenic action of the tumor microenvironment. Such inhibitors tackle the intrinsic complexity and heterogeneity of cancers and its intricate cooperative interaction with the microenvironment. This was indeed highlighted in a commentary in Oncogene. Since IGFIR and Stat3 function as drivers of many cancers both in the tumor and its microenvironment, these inhibitors are likely to be effective for many cancers. This family of inhibitors, especially NT219, is in development by TyrNovo of Israel since 2013 (www.tyrnovo.co.il) for a number of cancer indications, including EGFR kinase inhibitor resistant tumors.

Non-cancer indications

The Levitzki laboratory also proved the potential of tyrosine kinase inhibitors to treat non-malignant diseases such as restenosis (251,317,321,326,334), Psoriasis (177,222,265) and inflammatory conditions (218,238,249,252), avenues only recently begun to be taken up.

Targeting Polyinosine/Polycytosine to cancers

Another strategy to target cancer Levitzki has developed over the last decade is to target tumors with the synthetic double stranded RNA-PolyIC. This is done by using a polyethylenimine based vector that utilizes a ligand, which binds to a receptor that can internalize, as the homing device. The PolyIC loaded vector is internalized to the cancer cell, which overexpresses the receptor, induces the killing of the targeted cell as well as its neighboring tumor cells that do not express the target, because of the PolyIC induced bystander effects. The more robust neighboring normal cells remain unharmed. This strategy has been applied successfully, in animal studies, to strongly inhibit tumors overexpressing EGFR (341,365,368,378) Her2 (387,392) and PSMA396 (prostate membrane surface antigen). The revolutionary technology is in development by TargImmune Therapeutics AG (Basel, Switzerland) since 2016. A parallel strategy to target PolyIC is to tether the dsRNA-binding domain of the enzyme dsRNA dependent protein kinase to a receptor homing antibody as was recently demonstrated by Levitzki for PSMA395, which is overexpressed in metastatic prostate cancer.

T cell activation inhibitor

The Levitzki laboratory developed screening to search for inhibitors that target activated T cells but not quiescent T cells or other cell types. This screening is a biological screening and was not using a molecular target but rather looking for agents that inhibit Concanavalin A induced proliferation of PBMC and of Jurkat cells. The compound S101 was identified and indeed show to possess sub-micromolar inhibitory activity363. This compound was shown to rescue mice from superantigen induced shock394. Also, S101 inhibits T cell leukemia in mice.

Current Laboratory staff:

Laboratory Manager:
Klein Shoshana kleins@mail.ls.huji.ac.il
Senior Research Associates:
Shir Alexei alexeis@cc.huji.ac.il
MSc. Students:
Lital Friedman >
PhD Sutdents:
Edinger Noofar noofar.edinger@mail.huji.ac.il
Langut Yael ylangut@gmail.com
Post Doctoral Fellows:
Alaa Talhami talhamiala@gmail.com
Joubran Salim Salim.joubran@mail.huji.ac.il
Avi Weisberg
Neta Pessach
Revital Sasson
Zigler Maya ziglermaya@gmail.com
Technician:
Petcho Aviva apetcho@gmail.com

Former Laboratory staff:

MSc. Students:
Saar-Levy Inbal inbal.levy.s@gmail.com
Abeliovoch, Hagai
Aldouby, Yanir
Aviv Yoel yoelaviv@gmail.com
Bell, Michal
Ben-Ezry, Emilie emilie.benezry@mail.huji.ac.il
Capone, Ricardo
Friedrich, Inbar
Goldszal, Naomi
Gus, Yael
Hurwitz, Naama
Kashles, Ofra
Kravchenko-Balasha, Nataly
Man Matti mann2020@pob.huji.ac.il
Mizrachy-Schatrtz, Sarit
Rotnemer, Devarah
Sagiv-Barfi, Idit
Sajman, Yulia
Tenenbaum-Bayer, Hanna
Winograd-Katz, Sabina
Kirschner, Ilana
Feder, Deborah
Lifshits, Ruth
PhD Sutdents:
Flashner Efrat efrat.flashner@gmail.com
Abourbeh Galit galitha@md.huji.ac.il
Anafi, Motti
Arad, Hadas
Benhar, Moran benhar@duke.edu
Blum Galia galia@stanford.edu
Braun,Sergei sergei@vms.huji.ac.il
Chen, Irit
Dissoki Samar
Engelberg ,David
Epstein, Mike
Feder, Deborah
Friedrich Inbar inbarf@mail.ls.huji.ac.il
Geiger ,Tami tamig@pob.huji.ac.il
Goldberg, Doron
Gross Atan atan.gross@weizmann.ac.il
Gus ,Yael yaelgus@mail.com
Hanski, Emanuel emanuel.hanski@ekmd.huji.ac.il
Henis Yoav I. henis@post.tau.ac.il
Karni ,Rotem rotemka@ekmd.huji.ac.il
Kravchenko-Balalsha Nataly kravcn@pob.huji.ac.il
Mizrachy-Schwartz Sarit sarit4@gmail.com
Ortu, Giuseppina giuseppina_ortu@yahoo.it
Osherov, Nir
Perlman, Riki
Poraduso, Enrique
Reiss-Sklan Ela ella@novamed.co.il
Reuveni, Hadas hadas123@012.net.il
Segal, Marisa
Shelah, Noa noa@campus-bio.com>
Sherman Daniel daniel.sherman@mail.huji.ac.il
Shir, Alexei
Steiner, Lilach lilach.steiner@mail.huji.ac.il
Tal Gan Yftah yftah.t@gmail.com
Volberg, Tova
Winograd-Katz, Sabina Sabina.winograd-katz@weizmann.ac.il
Yablonski, Debby
Yaish, Pnina
Sagiv-BarfiI ,Idit idit@stanford.edu
Post Doctoral Fellows:
Atlas, Daphne  
Ben David, Iris Iris.ben.david@gmail.com
Friedman, Yael yaelfri@jexys.com
Livnah, Nurit
Lucassen, Andre andrelucassen@gmail.com
Makedonski, Kirill k_makedonski@yahoo.com
Newman, Michael
Reuveni, Hadas hadas123@012.net.il
Rimon, Gilad grimon@bgu.ac.il
Shir, Alexei alexeis@cc.huji.ac.il
Tolkovsky, Aviva M.
Weisberg, Avi aviw30@013net.net
Zenvirt, Shamir zenvirts@gmail.com /zenvirts@post.tau.ac.il
Former Research Associates:
Atlas, Daphne daphne.atlas@mail.huji.ac.il
Andre Lucassen
Keenan, Alan
Lester, Henry lester@Caltech.edu
Steer Michael, L. msteer@tuftsmedicalcenter.org
Administrative Assistants:
Aharon Ruth aruth@pob.huji.ac.il
Ben-Ezry Emilie emilie.benezry@mail.huji.ac.il
Sharon Cecile
Jaqueline Lazanov
Sultan-Swisa Liza lizas@savion.huji.ac.il
Technicians:
Bar-Sinai, Allan
Gal, Alma
Marbach, Irit
Sevilla, Nehama
Tal-Turkelltaub, Nathan
  1. 1968 : The validity of the "induced fit" hypothesis was demonstrated, using Concanavalin A (1968): Mn2+ induces the Ca2+ site, which in turn induces the formation of the sugar binding site ( 8 , 11 ).
  2. 1968-1980s : "Negative cooperativity" in enzymes and receptors was analyzed ( 16 , 33 , 38 , 54 , 64 , 90 , 102 , 160 ), initially with Daniel E.Koshland,Jr., and then in Levitzki's own laboratory. The molecular basis of this phenomenon was determined and "half-of-the-sites" reactivity, later to be found in many oligomeric proteins, was demonstrated in enzymes ( 20 , 32 , 91 ). Detailed mechanistic experiments on the mode of allosteric activation were performed ( 19 , 23 , 56 ). Levitzki developed quantitative approaches to study cooperativity in enzymes and a rigorous method to discriminate between molecular models of cooperativity, based on ligand competition experiments ( 74 ,89 ).
  3. 1974 : A radioligand binding assay for β-adrenoceptors was developed, on the basis of 3H-propranolol. This allowed, for the first time, the identification of these important and ubiquitous receptors ( 29 , 34 ).
  4. 1976-1978 : The β-adrenoceptor protein was identified for the first time, by using an effective radiolabeled affinity label ( 48 , 68 ).
  5. 1977-1990s : A comprehensive analysis of the mode of adenylyl cyclase activation by the receptors was undertaken; many of the issues were later found relevant to many other G protein activated systems. Among the issues analyzed was the molecular basis for partial agonism ( 79 ). The amplification mechanism, "collision coupling", which seems to apply to many other heterotrimeric G protein coupled effectors, was first described ( 57 , 65 , 76 , 75 , 77 , 78 , 81 , 87 , 98 , 110 , 121 , 272 ).
  6. 1982-1986 : The Levitzki group was the first to develop methodologies to reconstitute the β-receptor-G protein-cyclase ( 112 , 119 ), still the only receptor system to be reconstituted from its purified and separate components ( 122 , 123 , 124 , 125 , 135 , 136 ). This system reaffirmed the validity of the mode of coupling between the receptor and the Gs protein activated cyclase.
  7. 1980s-2000 : The role of Cdc25 as the Ras exchanger in S. cerevisiae was established ( 142 ), and the interacting domain in Ras was identified, using the yeast Cdc25/Ras system ( 208 , 226 ). Cdc25 phosphorylation was shown to be the feedback mechanism for the attenuation of glucose-induced cAMP formation. Another signal transduction pathway studied in S. cerevisiae is the pheromone pathway. The laboratory was the first to clone Ste5 ( 205 ), the first scaffold protein shown to function in a signal transduction pathway. It was shown that Ste5 dimerizes and that its dimerization is essential for signaling ( 238 ). Using the mating pathway, the laboratory also demonstrated that the G protein transmitting the pheromone signaling does not need to dissociate to α and βγ in order to function ( 272 ).
  8. 1987 onwards : Since the mid-1980s, the Levitzki laboratory has been developing the approach of "signal transduction therapy" ( 214 , 215, 223 ). The laboratory has developed protein tyrosine kinase inhibitors, also known as "tyrphostins" (tyrosine phosphorylation inhibitors), as lead compounds to combat proliferative diseases ( 157 , 159 , 206 , 213 , 234 and many more; see also reviews 223 , 224 , 310 and"selected publications" ). The group was also the first to demonstrate that PTK inhibitors that block Her-2/neu sensitize lung cancer cells to killing by the pro-apoptotic cytotoxic agents CDDP, doxorubicin and etoposide ( 236 ). Combining signal transduction inhibitors and cytotoxic agents is now a matter of routine, also in the clinic. The group, in collaboration with Sugen (now Pfizer), was the first to show the efficacy of VEGFR/KDR inhibitors as anti-angiogenic agents ( 235 ). The group was the first to demonstrate the anti-tumor effects in vivo (185 , 234 ). Tyrphostins also show efficacy against non-malignant proliferative diseases, like psoriasis ( 176 , 198 , 221 , 264 , 267 , 276 ), Papilloma ( 239 , 257 ) and restenosis ( 174 , 250 , 269 ), and as anti-inflammatory agents ( 217 , 243 , 248 , 308 ). The group pioneered the development of tyrosine kinase inhibitors for the treatment of CML ( 186 , 199 ), which formed the basis for the development of Gleevec in the late 1990s.
  9. 2000 onwards : The laboratory has established a technology to express cancer specific dsRNA, allowing the activation of the dsRNA-dependent protein kinase, PKR. This technology can in principle selectively kill cancer cells that harbor chromosomal aberrations ( 303 ). This approach is successful in inducing apoptosis in vitro and in vivo of glioblastoma multiforme (GBM) cancer cells expressing the truncated form of the EGF receptor. More recently the laboratory has established a technology to insert synthetic dsRNA molecules into cancer cells that over-express EGFR (365,368,373) Her2 (392) and PSMA (396), inducing their rapid demise. Two technologies are developed for targeting dsRNA to cells that overexpress receptors, which internalize upon ligand binding. One is based on the targeting of PolyIC bound to liganded polyethleneimine, where the ligand is EGF, EGFRaffibody, Her-2 affibody and DUPA, which targets prostate surface membrane antigen (PSMA). The second technology is using a chimeric protein composed of dsRNA binding domain tethered to EGF (393) or anti-PSMA single chain antibody (395).
  10. 2005 onwards : The laboratory is developing novel targeting agents that induce an irreversible degradation of a signaling protein on which the tumor depends. This has been achieved for the IGF1R/Irs1-2 pathway where the laboratory has generated an allosteric IGF1R kinase inhibitor, which induces the proteolytic destruction of Irs1 and Irs2. This inhibitor known as NT 157 and its potent analogs possess strong anti-tumor activity in experimental animals with human prostate cancer (385) and Plexxicon 4032 resistant metastatic melanoma (382). This technology was in pre-clinical development by Tyrnovo Therapeutics (founded by A.Levitzki) between 2005 and 2013, by TyrNovo Therapeutics (2013-2016) and Kitov Pharmaceuticals (since 2017). Recently it has been found that NT157 affects not only the tumor itself but also its microenvironment (391), actually acting as a double dagger anti-tumor agent. The reason that NT157 is so effective is due to the fact that it actually also acts as an anti-Stat3 agent. NT157 was found to induce the dephosphorylation of PY(705)Stat3, thus nullifying its actin in the tumor itself and in the conducive microenvironment. This is probably the reason why NT219 was found to be an excellent anti-tumor agent, inhibiting tumors that develop resistance to targeted therapies. This agent is currently in clinical development by TyrNovo Ltd. and Kitov Pharmaceuticals.
  11. In 2016 Levitzki co-founded TargImmune Therapeutics AG in Basel, Switzerland to bring targeted PolyIC to the clinic. Levitzki also published a fiction :”Shady Scientists “, available on Amazon and in Hebrew צללי מדענים

Alexander Levitzki,Ph.D,M.Sc

Professor of Biochemistry
Unit of Cellular Signaling
Department of Biological Chemistry
The Alexander Silberman Institute of Life Sciences
The Hebrew University of Jerusalem
Jerusalem 91904, Israel
Phone 972 2 6585 404
Fax 972 2 6512 958
Email: alex.levitzki@mail.huji.ac.il